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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2022.1029178</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>New insights into <italic>Chlamydia</italic> pathogenesis: Role of leukemia inhibitory factor</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Wang</surname>
<given-names>Jun</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/587174"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Katherine</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2036963"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Canadian Center for Vaccinology</institution>, <addr-line>Halifax, NS</addr-line>, <country>Canada</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Microbiology &amp; Immunology</institution>, <addr-line>Halifax, NS</addr-line>, <country>Canada</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Department of Pediatrics, Faculty of Medicine, Dalhousie University</institution>, <addr-line>Halifax, NS</addr-line>, <country>Canada</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Izaak Walton Killam (IWK) Health Centre</institution>, <addr-line>Halifax, NS</addr-line>, <country>Canada</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Guangming Zhong, The University of Texas Health Science Center at San Antonio, United States</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Kevin Hybiske, University of Washington, United States; Karthika Rajeeve, Rajiv Gandhi Centre for Biotechnology, India</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Jun Wang, <email xlink:href="mailto:jun.wang@dal.ca">jun.wang@dal.ca</email>
</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Molecular Bacterial Pathogenesis, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>18</day>
<month>10</month>
<year>2022</year>
</pub-date>
<pub-date pub-type="collection">
<year>2022</year>
</pub-date>
<volume>12</volume>
<elocation-id>1029178</elocation-id>
<history>
<date date-type="received">
<day>26</day>
<month>08</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>27</day>
<month>09</month>
<year>2022</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2022 Wang and Wang</copyright-statement>
<copyright-year>2022</copyright-year>
<copyright-holder>Wang and Wang</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>
<italic>Chlamydia trachomatis (Ct)</italic> is the leading cause of bacterial sexually transmitted infections worldwide. Since the symptoms of <italic>Ct</italic> infection are often subtle or absent, most people are unaware of their infection until they are tested or develop severe complications such as infertility. It is believed that the primary culprit of <italic>Ct</italic>-associated tissue damage is unresolved chronic inflammation, resulting in aberrant production of cytokines, chemokines, and growth factors, as well as dysregulated tissue influx of innate and adaptive immune cells. A member of the IL-6 cytokine family, leukemia inhibitory factor (LIF), is one of the cytokines induced by <italic>Ct</italic> infection but its role in <italic>Ct</italic> pathogenesis is unclear. In this article, we review the biology of LIF and LIF receptor (LIFR)-mediated signaling pathways, summarize the physiological role of LIF in the reproductive system, and discuss the impact of LIF in chronic inflammatory conditions and its implication in <italic>Ct</italic> pathogenesis. Under normal circumstances, LIF is produced to maintain epithelial homeostasis and tissue repair, including the aftermath of <italic>Ct</italic> infection. However, LIF/LIFR-mediated signaling &#x2013; particularly prolonged strong signaling &#x2013; can gradually transform the microenvironment of the fallopian tube by altering the fate of epithelial cells and the cellular composition of epithelium. This harmful transformation of epithelium may be a key process that leads to an enhanced risk of infertility, ectopic pregnancy and cancer following <italic>Ct</italic> infection.</p>
</abstract>
<kwd-group>
<kwd>
<italic>Chlamydia</italic>
</kwd>
<kwd>leukemia inhibitory factor (LIF)</kwd>
<kwd>ectopic pregnancy</kwd>
<kwd>infertility</kwd>
<kwd>cervical cancer</kwd>
<kwd>ovarian cancer</kwd>
<kwd>pelvic inflammatory disease (PID)</kwd>
</kwd-group>
<contract-sponsor id="cn001">Canadian Institutes of Health Research<named-content content-type="fundref-id">10.13039/501100000024</named-content>
</contract-sponsor>
<counts>
<fig-count count="4"/>
<table-count count="3"/>
<equation-count count="0"/>
<ref-count count="157"/>
<page-count count="13"/>
<word-count count="5894"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>The <italic>Chlamydiae</italic> family is a diverse group of obligatory intracellular bacteria, comprised of both pathogens and commensals, and found in varying habitats that can extend as far as the bottom of the Arctic Ocean (<xref ref-type="bibr" rid="B35">Dharamshi et&#xa0;al., 2020</xref>). <italic>Chlamydia trachomatis</italic> (<italic>Ct</italic>) is a human pathogen and the most common bacterial cause of sexually transmitted infections worldwide (<xref ref-type="bibr" rid="B144">WHO, 2021</xref>). An uptick in the reporting of chlamydial urogenital infections began in the 1990s following improvements in diagnostic technologies, and the rates have been increasing annually ever since (<xref ref-type="bibr" rid="B20">CDC, 2020</xref>; <xref ref-type="bibr" rid="B64">Huai et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B32">Control ECfDPa, 2022</xref>). <italic>Ct</italic> affects mostly young women aged 15-24, but can infect both men and women of all age groups (<xref ref-type="bibr" rid="B20">CDC, 2020</xref>; <xref ref-type="bibr" rid="B64">Huai et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B32">Control ECfDPa, 2022</xref>). Urogenital <italic>Ct</italic> infection is clinically associated with cervicitis, urethritis, endometritis, and salpingitis in women, and urethritis, proctitis and epididymitis in men (<xref ref-type="bibr" rid="B20">CDC, 2020</xref>; <xref ref-type="bibr" rid="B32">Control ECfDPa, 2022</xref>). However, <italic>Ct</italic> urogenital infections are notorious for being asymptomatic or sub-clinically symptomatic in as many as 70% of women and 50% of men (<xref ref-type="bibr" rid="B20">CDC, 2020</xref>; <xref ref-type="bibr" rid="B50">Gupta et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B32">Control ECfDPa, 2022</xref>). These &#x201c;silent&#x201d; <italic>Ct</italic> infections are often left untreated, which can last for months to years (<xref ref-type="bibr" rid="B96">McCormack et&#xa0;al., 1979</xref>; <xref ref-type="bibr" rid="B99">Morr&#xe9; et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B98">Molano et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B44">Geisler, 2010</xref>). Approximately 17% of <italic>Ct</italic>-infected women go on to develop pelvic inflammatory disease (PID) and serious complications such as tubal factor infertility (TFI), ectopic pregnancy and chronic pelvic pain (<xref ref-type="bibr" rid="B28">Cherpes et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B17">Brunham et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B117">Price et&#xa0;al., 2016</xref>). Repeated <italic>Ct</italic> infections and recurrent PID episodes are associated with a greater risk for adverse reproductive outcomes (<xref ref-type="bibr" rid="B59">Hillis et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B61">Hosenfeld et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B10">Batteiger et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B135">Trent et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B13">Bautista et&#xa0;al., 2018</xref>). Epidemiological evidence indicate that <italic>Ct</italic> infections significantly increase the risk of cervical (<xref ref-type="bibr" rid="B157">Zhu et&#xa0;al., 2016</xref>) and ovarian cancer (<xref ref-type="bibr" rid="B62">Hosseininasab-Nodoushan et&#xa0;al., 2021</xref>), presumably due to unresolved chronic inflammation (<xref ref-type="bibr" rid="B31">Clendenen et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B111">Peres et&#xa0;al., 2021</xref>). While considerable efforts have been made in attempts to elucidate <italic>Ct</italic> pathogenesis, there are still gaps regarding the definitive molecular and cellular mechanisms that cause <italic>Ct</italic>-associated tissue damage.</p>
<p>
<italic>Chlamydia</italic> species have a unique biphasic lifecycle consisting of an extracellular form of non-replicative but infectious elementary body (EB), and an intracellular form of replicative reticulate body (RB) (<xref ref-type="bibr" rid="B101">Moulder, 1991</xref>; <xref ref-type="bibr" rid="B52">Hackstadt et&#xa0;al., 1997</xref>). Infection is normally initiated at the single layer of mucosal epithelium in the lower genital tract, followed by bacterial ascension to the upper genital tract. Once inside the host cells, the non-replicative EB resides within a cytoplasmic inclusion body, where it differentiates into a replicative RB which then multiplies <italic>via</italic> binary fission. As an inclusion fills with progeny, RBs transform back into infectious EBs that are released from host cells to infect other neighboring cells (<xref ref-type="bibr" rid="B101">Moulder, 1991</xref>; <xref ref-type="bibr" rid="B52">Hackstadt et&#xa0;al., 1997</xref>). Immediately after intracellular infection, cell-autonomous immunity and innate defence mechanisms are triggered to fight against intracellular <italic>Ct</italic> infections (<xref ref-type="bibr" rid="B100">Mostowy and Shenoy, 2015</xref>; <xref ref-type="bibr" rid="B37">Elwell et&#xa0;al., 2016</xref>). These initial molecular and cellular events are followed by induction of <italic>Ct</italic>-specific adaptive humoral and cellular immune responses that are required for the ultimate elimination of intracellular <italic>Ct</italic> infection (<xref ref-type="bibr" rid="B73">Kelly, 2003</xref>; <xref ref-type="bibr" rid="B11">Batteiger et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B57">Helble and Starnbach, 2021</xref>). Notably, the inflammatory responses associated with innate and adaptive immunity are also involved in the tissue repair and regeneration processes (<xref ref-type="bibr" rid="B38">Eming et&#xa0;al., 2017</xref>), which are critical for removing the cellular debris from the infected tissue site, maintaining the tissue homeostasis, and restoring the normal structure and physiological integrity of the organ after infection (<xref ref-type="bibr" rid="B51">Gurtner et&#xa0;al., 2008</xref>). Of note, <italic>Chlamydia</italic> species are known for their strong ability to exploit various strategies to enhance intracellular survival (<xref ref-type="bibr" rid="B41">Fischer and Rudel, 2018</xref>; <xref ref-type="bibr" rid="B27">Chen et&#xa0;al., 2019</xref>). Some RBs ultimately differentiate into a morphologically distinct persistence form called an aberrant body (AB) in response to host defense molecules and certain antibiotic treatments (<xref ref-type="bibr" rid="B114">Phillips et&#xa0;al., 1984</xref>; <xref ref-type="bibr" rid="B95">Mazzoli et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B60">Hogan et&#xa0;al., 2004</xref>). While ABs are nonreplicative, they remain dormant inside host cells for a long period of time and are capable of reverting back to replicative RBs when more favorable conditions are present, such as the use of an immune suppressant (<xref ref-type="bibr" rid="B152">Yang et&#xa0;al., 1983</xref>; <xref ref-type="bibr" rid="B15">Beatty et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B83">Laitinen et&#xa0;al., 1996</xref>). As such, the host responses to <italic>Ct</italic> infection are complex and often modified by persistent infection, reactivation, and/or repeated exposures (<xref ref-type="bibr" rid="B128">Schuchardt and Rupp, 2018</xref>). The most widely accepted theory of <italic>Ct</italic> pathogenesis is that unresolved chronic inflammation is the primary culprit of <italic>Ct</italic>-associated tissue damage. This involves aberrant production of cytokines, chemokines, and growth factors, as well as the influx of innate and adaptive immune cells that collectively trigger aggravated wound healing and tissue repair processes (<xref ref-type="bibr" rid="B72">Karin and Clevers, 2016</xref>). While numerous cytokines have been implicated as part of the host response to <italic>Ct</italic> infection (<xref ref-type="bibr" rid="B151">Yang, 2003</xref>; <xref ref-type="bibr" rid="B148">Xiang et&#xa0;al., 2021</xref>), leukemia inhibitory factor (LIF), a member of the interleukin 6 (IL-6) cytokine family, has been largely ignored. Recent studies indicate that LIF is readily induced by <italic>Ct</italic> infection (<xref ref-type="bibr" rid="B58">Hess et&#xa0;al., 2001</xref>; <xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>), and that increased LIF expression is often linked to <italic>Ct</italic>-associated ectopic pregnancies in humans (<xref ref-type="bibr" rid="B121">Refaat et&#xa0;al., 2016</xref>) as well as severe oviductal pathology in mice (<xref ref-type="bibr" rid="B63">Hou et&#xa0;al., 2018</xref>). Therefore, LIF likely holds new perspectives of <italic>Ct</italic> pathogenesis. In this article, we review the biology of LIF and LIF receptor (LIFR)-mediated signaling pathways, summarize the physiological role of LIF in the reproductive system, and discuss the impact of LIF in chronic inflammatory conditions and its implication in <italic>Ct</italic> pathogenesis.</p>
</sec>
<sec id="s2">
<title>The biology of LIF and LIF receptors</title>
<p>LIF is encoded by a single copy gene on chromosome 22 in humans and chromosome 11 in mice (<xref ref-type="bibr" rid="B48">Gough et&#xa0;al., 1988</xref>; <xref ref-type="bibr" rid="B97">Metcalfe, 2011</xref>). The coding region is highly conserved among several mammalian species with more than 75% homology (<xref ref-type="bibr" rid="B146">Willson et&#xa0;al., 1992</xref>). LIF belongs to the IL-6 cytokine family that consists of IL-6, IL-11, IL-27, LIF, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1) (<xref ref-type="bibr" rid="B104">Nicola and Babon, 2015</xref>; <xref ref-type="bibr" rid="B125">Rose-John, 2018</xref>). All IL-6 family members utilize a receptor complex that is comprised of the shared signal-transducing receptor &#x3b2;-subunit gp130 (also known as IL-6R&#x3b2;), together with either a ligand-binding non-signaling receptor &#x3b1;-subunit and/or a signaling receptor &#x3b2;-subunit resembling gp130 for signal transduction. The specific composition of different ligand-receptor complexes underscores both redundant and unique biological activities of IL-6 family cytokines (<xref ref-type="bibr" rid="B125">Rose-John, 2018</xref>). In the case of LIF signaling, LIF binds to a receptor complex consisting of gp130 and LIFR, both of which are constitutively associated with receptor-associated JAK molecules, particularly JAK1 (<xref ref-type="bibr" rid="B122">Rodig et&#xa0;al., 1998</xref>; <xref ref-type="bibr" rid="B30">Chung et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B132">Takahashi et&#xa0;al., 2008</xref>), and initiates the signal transduction cascades that lead to activation of JAK/STAT3, MAPK and PI3K/AKT signaling pathways (<xref ref-type="bibr" rid="B104">Nicola and Babon, 2015</xref>). Notably, JAK/STAT3 signaling also induces the expression of suppressor of cytokine signaling 3 (SOCS3) (<xref ref-type="bibr" rid="B8">Babon et&#xa0;al., 2014</xref>), which binds to both JAK1 and gp130 and induces their ubiquitination and degradation, thereby shutting down entire signaling cascades (<xref ref-type="bibr" rid="B75">Kershaw et&#xa0;al., 2013</xref>) (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). While these pathways collectively contribute to cellular differentiation, survival and self-renewal, the qualitative and quantitative contributions of individual pathways are cell-type specific, leading to the pleiotropic effects of LIF (<xref ref-type="bibr" rid="B104">Nicola and Babon, 2015</xref>). Although named for its ability to inhibit proliferation of a myeloid leukemia cell line by inducing its terminal differentiation into macrophages (<xref ref-type="bibr" rid="B43">Gearing et&#xa0;al., 1987</xref>), LIF also regulates the growth and differentiation of embryonic stem cells (<xref ref-type="bibr" rid="B130">Smith et&#xa0;al., 1988</xref>; <xref ref-type="bibr" rid="B145">Williams et&#xa0;al., 1988</xref>), peripheral neurons (<xref ref-type="bibr" rid="B102">Murphy et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B89">Li et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B24">Cheng and Patterson, 1997</xref>), osteoblasts (<xref ref-type="bibr" rid="B94">Matsushita et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B129">Sims, 2020</xref>), adipocytes (<xref ref-type="bibr" rid="B49">Guo et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B154">Zeng et&#xa0;al., 2022</xref>), hepatocytes (<xref ref-type="bibr" rid="B12">Baumann and Wong, 1989</xref>), and endothelial cells (<xref ref-type="bibr" rid="B40">Ferrara et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B87">Li et&#xa0;al., 2022</xref>). This multifarious property of LIF has led to several rediscoveries of the protein and a variety of synonyms have been used in the older literature (<xref ref-type="bibr" rid="B3">Alexander et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B104">Nicola and Babon, 2015</xref>) (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). Since its original discovery, LIF has been shown to display a diverse range of biological activities in embryo implantation, bone metabolism and remodelling, immune regulation, as well as the development of uterine, hematopoietic, and nervous systems (<xref ref-type="bibr" rid="B81">Kurzrock et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B93">Mathieu et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B104">Nicola and Babon, 2015</xref>). The broad effects of LIF also coincide with ubiquitous expression of LIFR in The Human Protein Atlas (<xref ref-type="bibr" rid="B66">Human Protein Atlas, 2022</xref>) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>). However, contrary to the LIFR expression pattern, LIF expression is enriched in glandular and luminal cells in select healthy human tissues (<xref ref-type="bibr" rid="B66">Human Protein Atlas, 2022</xref>) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2B</bold>
</xref>). Overall, LIF production can be detected in many cell types, such as stromal fibroblasts (<xref ref-type="bibr" rid="B134">Tomida et&#xa0;al., 1984</xref>), bone marrow stromal cells (<xref ref-type="bibr" rid="B142">Wetzler et&#xa0;al., 1994</xref>), activated monocytes and macrophages (<xref ref-type="bibr" rid="B5">Anegon et&#xa0;al., 1990</xref>), astrocytes (<xref ref-type="bibr" rid="B141">Wesselingh et&#xa0;al., 1990</xref>), and T cells (<xref ref-type="bibr" rid="B43">Gearing et&#xa0;al., 1987</xref>).</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>LIF signaling. LIF signaling occurs through a receptor complex of gp130 and LIFR. Under resting conditions, both receptor chains are constitutively associated with inactivated JAK1 molecules. Upon LIF stimulation, LIF binds to LIFR and gp130 and initiates signal transduction by transactivation of the gp130-bound and LIFR-bound JAK1 molecules. JAK1 then phosphorylates five tyrosine molecules on each receptor chain, which create the docking sites for the transcription factors STAT3 and SHP-2, leading to activation of JAK/STAT3, MAPK and PI3K/AKT signaling pathways. The docking site also recruits transcription factor SOCS3, which is a predominant negative pathway that inhibits JAK-STAT3 activation. By controlling cellular differentiation, survival and self-renewal, these pathways collectively contribute to specific physiological and immunological processes such as tissue homeostasis, hematopoiesis, pregnancy, bone remodeling, neuromuscular system, inflammatory conditions, and cancer (<xref ref-type="bibr" rid="B104">Nicola et al., 2015</xref> and <xref ref-type="bibr" rid="B125">Rose-John et al., 2018</xref>).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-1029178-g001.tif"/>
</fig>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Synonyms for LIF.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Abbreviation</th>
<th valign="top" align="center">Name</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">LIF</td>
<td valign="top" align="left">Leukemia inhibitory factor</td>
</tr>
<tr>
<td valign="top" align="left">D-factor</td>
<td valign="top" align="left">Differentiation-inducing factor</td>
</tr>
<tr>
<td valign="top" align="left">DIF</td>
<td valign="top" align="left">Differentiation-inducing factor</td>
</tr>
<tr>
<td valign="top" align="left">DIA</td>
<td valign="top" align="left">Differentiation inhibitory activity</td>
</tr>
<tr>
<td valign="top" align="left">DRF</td>
<td valign="top" align="left">Differentiation-retarding factor</td>
</tr>
<tr>
<td valign="top" align="left">MLPLI</td>
<td valign="top" align="left">Melanoma-derived lipoprotein lipase inhibitor</td>
</tr>
<tr>
<td valign="top" align="left">HILDA</td>
<td valign="top" align="left">Human interleukin for DA-1 cells</td>
</tr>
<tr>
<td valign="top" align="left">CDF</td>
<td valign="top" align="left">Cholinergic differentiation factor</td>
</tr>
<tr>
<td valign="top" align="left">OAL</td>
<td valign="top" align="left">Osteoclast-activating factor</td>
</tr>
<tr>
<td valign="top" align="left">HSF-III</td>
<td valign="top" align="left">Hepatocyte-stimulating factor III</td>
</tr>
</tbody>
</table>
</table-wrap>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>LIFR and LIF expression in human tissues. The transcripts of LIFR and LIF in 55 healthy human tissues are displayed at normalized expression levels (nTPM) that are created by combining transcriptomics datasets of The Human Protein Atlas (HPA) project and The Genotype-Tissue Expression (GTEx) project. Figure is available from The Human Protein Atlas website (accessed on August 15, 2022).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-1029178-g002.tif"/>
</fig>
</sec>
<sec id="s3">
<title>The role of LIF/LIFR in the female reproductive system</title>
<p>Menstruation is a key feature of the mammalian female reproductive system that is characterized by monthly remolding, shedding and regeneration of the endometrium under the influence of ovarian hormones and divided into an estrogen (E2)-dominated proliferative phase and a progesterone (P4)-dominated secretory phase (<xref ref-type="bibr" rid="B120">Reed and Carr, 2000</xref>). Cell types in the human endometrium include epithelial cells, stromal fibroblasts, immune cells, vascular endothelium, vascular smooth muscle cells and stem/progenitor cells. The epithelial cells are further divided into three subpopulations: luminal epithelium, glandular epithelium, and ciliated epithelial cells (<xref ref-type="bibr" rid="B140">Wang et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B47">Giudice, 2020</xref>). Functionally, the glandular and luminal epithelia are required for embryo attachment whereas the ciliated epithelial cells are needed to facilitate sperm transport, fluid movement and removal of debris from the uterine cavity (<xref ref-type="bibr" rid="B47">Giudice, 2020</xref>). During the menstrual cycle, the human endometrium undergoes a decidualization process, which is characterized by the transformation of stromal cells to round epithelioid cells capable of secreting growth hormones (e.g., prolactin and insulin-like growth factor binding protein-1), an influx of specialized uterine natural killer cells, and vascular remodeling to support the maternal blood supply to the growing embryo (<xref ref-type="bibr" rid="B106">Okada et&#xa0;al., 2018</xref>). The decidua plays a critical role in regulating trophoblast invasion, modulating the local immune response at the fetal-maternal interface, and development of the placenta (<xref ref-type="bibr" rid="B119">Ramathal et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B106">Okada et&#xa0;al., 2018</xref>). The human decidua is formed routinely and is shed off in the absence of an embryo in the endometrium, whereas the decidua is only formed upon embryo implantation in mice (<xref ref-type="bibr" rid="B119">Ramathal et&#xa0;al., 2010</xref>). While the steroid hormones E2 and P4 have paramount effects on the development and differentiation of decidua, the hormone effects are also mediated either directly or indirectly through locally produced growth factors and cytokines (<xref ref-type="bibr" rid="B84">Large and DeMayo, 2012</xref>). LIF is one of the most important cytokines essential for decidualization, embryo implantation, and regulation of immune tolerance at the fetal-maternal interface (<xref ref-type="bibr" rid="B131">Stewart et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B1">Aghajanova, 2004</xref>; <xref ref-type="bibr" rid="B77">Kimber, 2005</xref>).</p>
<p>In healthy women, LIF mRNA and protein are expressed by the endometrium throughout the menstrual cycle, with a striking increase in the mid-secretory to late-secretory phase (<xref ref-type="bibr" rid="B21">Charnock-Jones et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B139">Vogiagis et&#xa0;al., 1996</xref>) which is a finite period defined as the implantation window (<xref ref-type="bibr" rid="B56">Harper, 1992</xref>). Single-cell transcriptomic analysis of the human endometrium during the menstrual cycle has revealed an abrupt and strong transcriptomic activation in epithelial cells, and a widespread decidualization feature in the stromal cells during the implantation window (<xref ref-type="bibr" rid="B140">Wang et&#xa0;al., 2020</xref>). LIF mRNA is most abundantly expressed in the glandular and luminal epithelial cells (<xref ref-type="bibr" rid="B66">Human Protein Atlas, 2022</xref>) (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>), and the same expression pattern is detected by immunohistochemistry staining (<xref ref-type="bibr" rid="B21">Charnock-Jones et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B139">Vogiagis et&#xa0;al., 1996</xref>). In parallel with the pattern of LIF expression, LIFR also peaks in human endometrium during the mid-secretory phase (<xref ref-type="bibr" rid="B21">Charnock-Jones et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B33">Cullinan et&#xa0;al., 1996</xref>), with strong expression in endothelial cells, intermediate levels in glandular epithelial cells, luminal epithelial cells and smooth muscle cells, but very low levels in immune cells (<xref ref-type="bibr" rid="B66">Human Protein Atlas, 2022</xref>) (<xref ref-type="fig" rid="f3">
<bold>Figure&#xa0;3</bold>
</xref>). While the tumor suppressor gene p53 is required to maintain both basal and inducible transcription of LIF in the uterus (<xref ref-type="bibr" rid="B65">Hu et&#xa0;al., 2007</xref>), endometrial expression of LIF and LIFR are induced by E2 (<xref ref-type="bibr" rid="B22">Chen et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B36">Ding et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B85">Liang et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B153">Yoo et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B116">Polim et&#xa0;al., 2022</xref>) and P4 (<xref ref-type="bibr" rid="B36">Ding et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B153">Yoo et&#xa0;al., 2019</xref>), respectively. Interestingly, P4 also induces LIF expression in bovine endometrium epithelial cells <italic>in vitro (</italic>
<xref ref-type="bibr" rid="B39">Feng et&#xa0;al., 2022</xref>). As such, the concerted physiological effects of E2 and P4 in the reproductive system are executed, if not entirely, <italic>via</italic> regulation of LIF/LIFR signaling pathways, particularly the JAK-STAT3 pathway (<xref ref-type="bibr" rid="B23">Cheng et&#xa0;al., 2001</xref>). LIF activates over 40 different transcription factors that control a multitude of physiological pathways and signal cascades for epithelial polarity and apoptosis, epithelial-mesenchymal interaction, angiogenesis, stromal decidualization and cell proliferation, creating a favorable environment in the uterus to promote embryo implantation (<xref ref-type="bibr" rid="B123">Rosario et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B127">Salleh and Giribabu, 2014</xref>; <xref ref-type="bibr" rid="B124">Rosario and Stewart, 2016</xref>).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>LIF and LIFR mRNA expression in different cell types of the human endometrium. The transcripts of LIF and LIFR in healthy human endometrial tissues are displayed at normalized expression levels (nTPM). Cell types in the endometrium include epithelial cells (blue), stromal fibroblasts (green), immune cells (red), vascular endothelium (purple), and vascular smooth muscle cells (orange). The epithelial cells are further divided into luminal epithelium, glandular epithelium and ciliated epithelial cells. The ciliated epithelial cell clusters are highlighted in yellow boxes. Figure is available from The Human Protein Atlas website (accessed on August 15, 2022).</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-1029178-g003.tif"/>
</fig>
<p>Functional LIFR and gp130 are expressed on both luminal and granular epithelial cells, human oocytes and preimplantation embryos (<xref ref-type="bibr" rid="B137">van Eijk et&#xa0;al., 1996</xref>). This expression pattern suggests that LIF/LIFR-mediated signaling pathways may promote embryo implantation <italic>via</italic> both autocrine and paracrine pathways. Several studies using gene-deficient mice and embryo-transfer approaches indicate that maternal LIF/LIFR-mediated signaling pathways are essential in embryo implantation (<xref ref-type="bibr" rid="B131">Stewart et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B25">Cheng et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B26">Cheng et&#xa0;al., 2017</xref>). Both LIF-deficient mice (<xref ref-type="bibr" rid="B131">Stewart et&#xa0;al., 1992</xref>) and mice with LIFR-deficiency specifically in luminal and glandular epithelial cells (<xref ref-type="bibr" rid="B26">Cheng et&#xa0;al., 2017</xref>), fail to support embryo implantation and development. However, the development of LIF-deficient embryos in LIF-deficient mice can be rescued by recombinant LIF injections (<xref ref-type="bibr" rid="B22">Chen et&#xa0;al., 2000</xref>). In accordance with the animal studies, reduced LIF production is observed in women with unexplained infertility and recurrent miscarriages compared to healthy fertile women in many studies (<xref ref-type="bibr" rid="B82">Laird et&#xa0;al., 1997</xref>; <xref ref-type="bibr" rid="B54">Hambartsoumian, 1998</xref>; <xref ref-type="bibr" rid="B147">Wu et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B91">Margioula-Siarkou et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B92">Margioula-Siarkou et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B4">Alzaidi et&#xa0;al., 2021</xref>), although there are exceptions (<xref ref-type="bibr" rid="B107">Olivennes et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B150">Xu et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B71">Karaer et&#xa0;al., 2014</xref>). Interestingly, certain LIF polymorphisms have been associated with recurrent implantation failure (<xref ref-type="bibr" rid="B136">Vagnini et&#xa0;al., 2019</xref>) and women with LIF mutations also have poor success rates of implantation and fertilization (<xref ref-type="bibr" rid="B46">Giess et&#xa0;al., 1999</xref>; <xref ref-type="bibr" rid="B105">Novotn&#xfd; et&#xa0;al., 2009</xref>) (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>).</p>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Influence of LIF in human infertility, miscarriage and assisted pregnancy Brief description of the study.</p>
</caption>
<table frame="hsides">
<tbody>
<tr>
<td valign="top" align="left">Normal fertile women, women with unexplained infertility and women who suffered recurrent miscarriages were studied. Researchers obtained uterine flushings from all the women for analysis. LIF in flushings obtained from women with unexplained infertility was significantly lower than normal fertile women. They concluded that decreased concentrations of LIF in women with unexplained infertility indicate how important the cytokine is to embryo implantation.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B82">Laird et&#xa0;al., 1997</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">32 women with unexplained infertility and 17 fertile women were studied. Endometrial biopsy samples were obtained and studied using a sensitive enzyme-linked immunosorbent assay (ELISA). LIF secretion was 2.2 times higher during the secretory phase than proliferative phase in fertile women whereas infertile women did not have this elevation in cytokine production. They concluded that the deregulation of endometrial LIF secretion may be linked to unexplained infertility and repetitive failures of implantation.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B54">Hambartsoumian, 1998</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">30 infertile women with multiple implantation failures (MIF) and a fertile control group were studied. Researchers obtained endometrial biopsies in the proliferative phase and measured expression of LIF using immunohistochemistry and western blotting. Lower expression of LIF was found in infertile women with MIF compared to fertile women. They determined that initial lower expression of LIF during the proliferative phase may be a cause of multiple failures of implantation.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B147">Wu et&#xa0;al., 2013</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Women diagnosed with infertility and a control group of fertile women were studied. Researchers took an endometrial biopsy post ovulation to examine LIF and LIF-R expression. No significant differences in LIF/LIF-R was found in the stromal cells but there was a significant reduction in LIF/LIF-R expression in infertile women in epithelial cells. They concluded that LIF and LIF-R are significantly under expressed in epithelial cells of infertile women.&#xa0;</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B92">Margioula-Siarkou et&#xa0;al., 2017</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">75 infertile women and 40 control women were studied. Levels of LIF and IL-11 were examined using qRT-PCR. Lower levels of LIF and IL-11 were linked to increased risk of having PCOS, tubal factor, and unexplained fertility, likely due to the critical role these genes play in embryo implantation.&#xa0;</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B4">Alzaidi et&#xa0;al., 2021</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">30 women with idiopathic recurrent pregnancy loss (RPL) and 30 fertile controls were studied. Endometrial biopsies were used to evaluate PROK1 and LIF expression. PROK1 and LIF expression was significantly increased in the endometriums of women with idiopathic RPL. They concluded that increased mRNA expression of PROK1 and LIF could contribute to risk of RPL.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B71">Karaer et&#xa0;al., 2014</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">148 IVF patients received uterine flushing during egg retrieval to assess LIF levels. Uterine flushing did not appear to affect pregnancy rates. LIF was found in 46% of patients at time of sample collection but no indication of better pregnancy rates in patients that had LIF compared to those who did not.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B107">Olivennes et&#xa0;al., 2003</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Women who were undergoing assisted reproduction were studied. Researchers obtained endometrial biopsies from women with recurrent pregnancy loss and a control group of fertile women, 7 days after luteinizing hormone peaked and LIF expression was examined. There was no significant difference in LIF expression between the two study groups.</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B150">Xu et&#xa0;al., 2012</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">44 women with recurrent implantation failure (RIF), 63 women who had children <italic>via</italic> IVF and 65 fertile women with children and no history of miscarriage were studied. Women who had a polymorphism in ESR1 and LIF had increased chances of presenting with RIF. They concluded that ER1 and LIF polymorphisms can predict RIF.&#xa0;</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B136">Vagnini et&#xa0;al., 2019</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Women from 4 different groups of diagnoses associated with LIF mutations and various causes of infertility were studied to determine the impact of mutation in the LIF gene on assisted pregnancy <italic>via in vitro</italic> fertilization (IVF). They concluded that women with LIF mutations, infertility and endometriosis have poorer outcomes with IVF than other groups.&#xa0;</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B105">Novotn&#xfd; et&#xa0;al., 2009</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Nulligravid infertile women, a fertile control group and unrelated control group were screened for LIF gene mutations. 3 point-mutations were identified in the infertile group that reduced biological activity of the LIF protein. They concluded that a heterozygous LIF mutation could result in decreased availability of LIF in the uterus, leading to implantation failure and thus infertility.&#xa0;</td>
<td valign="top" align="center">
<xref ref-type="bibr" rid="B46">Giess et&#xa0;al., 1999</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Although the collective evidence support a critical role for LIF in promoting embryo implantation, recombinant human LIF did not yield any beneficial effects in one randomized, double-blind, placebo-controlled, multicenter study (<xref ref-type="bibr" rid="B16">Brinsden et&#xa0;al., 2009</xref>). Surprisingly, recombinant LIF, administered to infertile women subcutaneously for 7 days starting on the day of embryo transfer, significantly reduced clinical pregnancy rates (<xref ref-type="bibr" rid="B16">Brinsden et&#xa0;al., 2009</xref>). Although the reason behind this unexpected result remains to be investigated, it is possible that a balanced LIF/LIFR signal is critical for successful pregnancies; both too little and too much LIF production can cause infertility. A prolonged strong LIF signal may trigger activation of a negative feedback pathway mediated by SOCS, subsequently promoting degradation of receptors, leading to implantation failure (<xref ref-type="bibr" rid="B19">Carvalho et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B155">Zhao et&#xa0;al., 2021</xref>). Furthermore, implantation is a complex and highly organized process that involves active crosstalk between a receptive uterus and a competent blastocyte in a time- and location-specific manner (<xref ref-type="bibr" rid="B78">Kim and Kim, 2017</xref>). Thus, dysregulation of LIF/LIFR may lead to ectopic pregnancy and potentially other fertility-related issues (<xref ref-type="bibr" rid="B80">Krishnan et&#xa0;al., 2013</xref>).</p>
</sec>
<sec id="s4">
<title>The potential impact of LIF/LIFR axis in <italic>Ct</italic> pathogenesis</title>
<p>In addition to its physiological roles, the LIF/LIFR axis has been broadly discussed in the context of chronic inflammation, including chronic airway inflammation (<xref ref-type="bibr" rid="B79">Knight, 2001</xref>), cutaneous inflammation (<xref ref-type="bibr" rid="B156">Zhu et&#xa0;al., 2001</xref>), neuroinflammation (<xref ref-type="bibr" rid="B88">Linker et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B109">Pan et&#xa0;al., 2008</xref>), and cancer-associated inflammation (<xref ref-type="bibr" rid="B29">Christianson et&#xa0;al., 2021</xref>), mostly as an anti-inflammatory cytokine. In infection models, LIF is recognized as a vital stem cell growth factor that protects the lung from collateral damage during inflammatory attack against viral infections (<xref ref-type="bibr" rid="B118">Quinton et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B42">Foronjy et&#xa0;al., 2014</xref>).</p>
<p>The production of LIF during chlamydial infection has been reported by several <italic>in vitro</italic> and <italic>in vivo</italic> studies (<xref ref-type="bibr" rid="B58">Hess et&#xa0;al., 2001</xref>; <xref ref-type="bibr" rid="B113">Peters et&#xa0;al., 2005</xref>; <xref ref-type="bibr" rid="B121">Refaat et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B63">Hou et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>). It was first identified through comparing the transcriptomic profile of 1176 genes in DNA arrays of <italic>Ct</italic>-infected and mock-infected epithelial HeLa cells, in which 18 genes, including LIF, were up-regulated by <italic>Ct</italic> infection (<xref ref-type="bibr" rid="B58">Hess et&#xa0;al., 2001</xref>). This observation has been recently confirmed in human fallopian tube organoid cultures (<xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>), which provide a novel <italic>in vitro</italic> system for recapitulating <italic>Ct</italic> infection <italic>in vivo</italic>. It was demonstrated that LIF is readily induced by <italic>Ct</italic> infection, along with robust activation of type I interferon (IFN-&#x3b2;) signaling and upregulation of inducible nitric oxide synthase (NOS2) to control <italic>Ct</italic> replication in organoids. In addition, LIF/LIFR signaling is involved in tissue injury and repair responses that are needed for maintaining epithelial homeostasis and organoid renewal (<xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>). Therefore, LIF seems to be part of cell-autonomous immunity, and its production is a protective response. Notably, LIF production is only triggered in mice by a pathological, plasmid-containing <italic>Chlamydia muridarum</italic>, but not a plasmid-free one. The level of LIF is closely associated with the degree of bacterial ascension in the upper genital tract and the formation of hydrosalpinx (<xref ref-type="bibr" rid="B63">Hou et&#xa0;al., 2018</xref>), a common tissue pathology associated with <italic>Ct</italic> infection in both humans and mice that can cause infertility. Similarly, LIF mRNA and protein are most detected at high levels in human fallopian tube samples obtained from ectopic pregnancies associated with <italic>Ct</italic> infections but not non-<italic>Ct</italic> infections (<xref ref-type="bibr" rid="B121">Refaat et&#xa0;al., 2016</xref>). While these experimental results support a potential role of LIF in <italic>Ct</italic> pathogenesis, it is intriguing why a protective response is highly associated with tissue pathology.</p>
<p>The human fallopian tube is a conduit that has a major functional role in oocyte pickup, fertilization, and embryo transport. The fallopian tube mucosa contains two major histologic cell types: ciliated epithelial cells and secretory epithelial cells, which work together for effective tubal transport of ova, sperm, and embryos for successful spontaneous pregnancy (<xref ref-type="bibr" rid="B90">Lyons et&#xa0;al., 2006</xref>). Propulsion of gametes and embryos is achieved by complex interactions between muscle contractions, ciliary activity, and the flow of tubal secretions. Proper density of ciliated cells is required to avoid ectopic pregnancy (<xref ref-type="bibr" rid="B90">Lyons et&#xa0;al., 2006</xref>). It has been demonstrated that fallopian tubes containing an ectopic pregnancy have a marked reduction in the number of ciliated cells in comparison with those of women with an intrauterine gestation (<xref ref-type="bibr" rid="B138">Vasquez et&#xa0;al., 1983</xref>; <xref ref-type="bibr" rid="B90">Lyons et&#xa0;al., 2006</xref>). Detailed ultrastructural analysis of hydrosalpinx of infertile women also demonstrates severe abnormalities in epithelial cells, including flattening of the epithelial layer and severe loss of ciliated cells (<xref ref-type="bibr" rid="B2">Ajonuma et&#xa0;al., 2005</xref>). Notably, ciliated cells and secretory cells are developmentally connected. A study using <italic>in vivo</italic> genetic cell lineage tracing in mice demonstrated that secretory epithelial cells not only self-renew, but also give rise to ciliated epithelial cells (<xref ref-type="bibr" rid="B45">Ghosh et&#xa0;al., 2017</xref>). LIF/LIFR signaling has been shown to alter the fate of epithelial cells during <italic>Ct</italic> infection (<xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>). The density of ciliated cells in organoids chronically infected with <italic>Ct</italic> is markedly reduced compared to non-infected controls (<xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>). This is likely mediated by LIF, as addition of recombinant LIF protein to non-infected organoids potently inhibits the frequency of ciliated cells (<xref ref-type="bibr" rid="B76">Kessler et&#xa0;al., 2019</xref>). The results from the organoid cultures provide strong experimental evidence supporting a potential role of LIF in epithelial transformation during <italic>Ct</italic> infection.</p>
<p>LIF is also recognized as a cell-autonomous molecule during intracellular viral infections caused by HIV (<xref ref-type="bibr" rid="B110">Patterson et&#xa0;al., 2002</xref>; <xref ref-type="bibr" rid="B133">Tjernlund et&#xa0;al., 2006</xref>) and HPV (<xref ref-type="bibr" rid="B14">Bay et&#xa0;al., 2011</xref>). We were unable to find any reports on LIF production caused by extracellular pathogens, such as <italic>Neisseria gonorrhoeae</italic>. Therefore, it is likely that LIF is produced preferentially, if not exclusively, upon intracellular infections for combating intracellular pathogens and assisting in tissue repair and epithelium homeostasis. While this is a protective response in nature, repeated <italic>Ct</italic> infections and/or persistent <italic>Ct</italic> infections may lead to aberrant expression of LIF and LIF-mediated alterations of the epithelium, which has been demonstrated in <italic>in vitro</italic> models of persistent chlamydial infections (<xref ref-type="bibr" rid="B113">Peters et&#xa0;al., 2005</xref>). Clinical observations indicate that most women with TFI and serological evidence of <italic>Ct</italic> infection lack a history of clinical PID (<xref ref-type="bibr" rid="B18">Brunham et&#xa0;al., 1985</xref>). Therefore, it is likely that the regulation of LIF and LIF-mediated responses are operating for long periods of time, during which, LIF levels are constantly being modified by surrounding proinflammatory cytokines and growth factors (<xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref>). LIF expression is robustly induced by proinflammatory signals (e.g., LPS, IL-1 and TNF-&#x3b1;) (<xref ref-type="bibr" rid="B143">Wetzler et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B67">Ishimi et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B55">Hamilton et&#xa0;al., 1993</xref>; <xref ref-type="bibr" rid="B142">Wetzler et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B112">Perrier d'Hauterive et&#xa0;al., 2004</xref>) and signaling molecules active in tissue growth and development, including platelet-derived growth factor (PDGF) (<xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>), epidermal growth factor (EGF) (<xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>), human chorionic gonadotropin (hCG) (<xref ref-type="bibr" rid="B112">Perrier d'Hauterive et&#xa0;al., 2004</xref>), insulin-like growth factor (IGF) (<xref ref-type="bibr" rid="B112">Perrier d'Hauterive et&#xa0;al., 2004</xref>), and transforming growth factor-&#x3b2; (TGF-&#x3b2;) (<xref ref-type="bibr" rid="B143">Wetzler et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B112">Perrier d'Hauterive et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B126">Ruan et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B108">Ota et&#xa0;al., 2013</xref>). Many of these molecules are concurrently induced by <italic>Ct</italic> infection, which collectively amplify LIF expression and LIFR-mediated responses, and eventually lead to a marked reduction in ciliated epithelial cells and an increase of secretory epithelial cells in the fallopian tube. In comparison, IFN-&#x3b3; potently supresses LIF expression in endometrial epithelial cells and stromal cells <italic>in vitro (</italic>
<xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>). Of note, IL-4 is a typical type 2 cytokine that regulates LIF in a cell type-dependent manner. IL-4 downregulates LIF in cultured bone marrow stromal cells, synovial fibroblasts and liver myofibroblasts (<xref ref-type="bibr" rid="B142">Wetzler et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B34">Denizot et&#xa0;al., 1999</xref>), whereas it upregulates LIF secretion in type 2 helper T-cells (<xref ref-type="bibr" rid="B115">Piccinni et&#xa0;al., 1998</xref>). Given that IFN-&#x3b3; and IL-4 are primarily produced by T cells, it is possible that LIF production may diminish upon the establishment of adaptive immune responses. While LIF has been shown to promote regulatory T cells and inhibit the differentiation of type 17 helper T-cells (<xref ref-type="bibr" rid="B97">Metcalfe, 2011</xref>), it is unclear how T cell responses are regulated by prolonged LIF production during <italic>Ct</italic> infection. Although only limited knowledge is available, the crosstalk between LIF and T cells is likely an integral part of <italic>Ct</italic> pathogenesis and additional studies are warranted.</p>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Regulation of LIF expression.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Factor</th>
<th valign="top" align="center">Effect</th>
<th valign="top" align="center">Citation</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">p53</td>
<td valign="top" align="left">p53-knockout female mice show impaired fertility and reduced basal and induced LIF expression in uteri.</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B65">Hu et&#xa0;al., 2007</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Estrogen/Estradiol (E2)</td>
<td valign="top" align="left">E2 injections induces LIF expression in uterine tissues following E2 injections</td>
<td valign="top" align="left">References<break/>
<xref ref-type="bibr" rid="B22">Chen et&#xa0;al., 2000</xref>; <xref ref-type="bibr" rid="B36">Ding et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B85">Liang et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B153">Yoo et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B116">Polim et&#xa0;al., 2022</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Progesterone (P4)</td>
<td valign="top" align="left">P4 induces LIF expression in bovine endometrium epithelial cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B39">Feng et&#xa0;al., 2022</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Platelet derived growth factor</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">epidermal growth factor (EGF)</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Chorionic gonadotropin</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B112">Peerier d'Hauterive et al., 2004</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">Insulin-like growth factor</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B112">Peerier d'Hauterive et al., 2004</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">TGF-&#x3b2;</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells, bone marrow stromal cells, and murine osteoblast cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">References <xref ref-type="bibr" rid="B126">Ruan et al., 2010</xref>; <xref ref-type="bibr" rid="B143">Wetzler et al., 1991</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>; <xref ref-type="bibr" rid="B112">Perrier d'Hauterive et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B108">Ota et&#xa0;al., 2013</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">IL-1</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells, bone marrow stromal cells, osteoblasts and synovial fibroblasts <italic>in vitro</italic>
</td>
<td valign="top" align="left">References <xref ref-type="bibr" rid="B143">Wetzler et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B67">Ishimi et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B55">Hamilton et&#xa0;al., 1993</xref>; <xref ref-type="bibr" rid="B142">Wetzler et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">TNF</td>
<td valign="top" align="left">Upregulates LIF in human endometrium epithelial cells and stromal cells, bone marrow stromal cells, osteoblasts and synovial fibroblasts <italic>in vitro</italic>
</td>
<td valign="top" align="left">References <xref ref-type="bibr" rid="B143">Wetzler et&#xa0;al., 1991</xref>; <xref ref-type="bibr" rid="B67">Ishimi et&#xa0;al., 1992</xref>; <xref ref-type="bibr" rid="B55">Hamilton et&#xa0;al., 1993</xref>; <xref ref-type="bibr" rid="B142">Wetzler et&#xa0;al., 1994</xref>; <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">LPS/Endotoxin</td>
<td valign="top" align="left">Upregulates LIF in osteoblasts <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B67">Ishimi et al., 1992</xref>
</td>
</tr>
<tr>
<td valign="top" align="left">IFN-&#x264;</td>
<td valign="top" align="left">Inhibits LIF in human endometrium epithelial cells and stromal cells <italic>in vitro</italic>
</td>
<td valign="top" align="left">Reference <xref ref-type="bibr" rid="B6">Arici et&#xa0;al., 1995</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Based on the collective evidence discussed above, it is appealing to suggest that the LIF-mediated reduction in ciliated epithelial cell density is a key process of <italic>Ct</italic> pathogenesis, which can lead to reduced opportunities for fertilization and increased risk of ectopic pregnancy. Although it remains to be demonstrated experimentally, increased secretory cell density may lead to over-production and accumulation of fluids inside the fallopian tube, a characteristic feature of hydrosalpinx (<xref ref-type="bibr" rid="B103">Ng and Cheong, 2019</xref>). Consistent with this notion, LIF is found to be expressed in human fallopian tubes (<xref ref-type="bibr" rid="B74">Keltz et&#xa0;al., 1996</xref>) and is markedly elevated in chronically inflamed fallopian tubes (<xref ref-type="bibr" rid="B68">Ji et&#xa0;al., 2009</xref>). Furthermore, ectopic pregnancies are mostly associated with intracellular infections caused by <italic>Ct</italic> and <italic>Mycoplasma genitalium</italic>, and less frequently linked to extracellular pathogens like <italic>Neisseria gonorrhoeae</italic> (<xref ref-type="bibr" rid="B7">Ashshi et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B121">Refaat et&#xa0;al., 2016</xref>), despite its ability to cause a similar spectrum of pelvic inflammatory diseases (<xref ref-type="bibr" rid="B149">Xu and Gray-Owen, 2021</xref>).</p>
<p>The Human Protein Atlas dataset shows that high expression of LIF is a poor prognostic marker for human cervical cancer (<xref ref-type="bibr" rid="B66">Human Protein Atlas, 2022</xref>), for which HPV and <italic>Ct</italic> are well-known risk factors (<xref ref-type="bibr" rid="B157">Zhu et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B86">Liao et&#xa0;al., 2022</xref>). <italic>Ct</italic> infection is also a risk factor for ovarian cancer (<xref ref-type="bibr" rid="B62">Hosseininasab-Nodoushan et&#xa0;al., 2021</xref>). While HPV promotes cervical cancer <italic>via</italic> oncogenic transformation (<xref ref-type="bibr" rid="B9">Baedyananda et&#xa0;al., 2022</xref>), <italic>Ct</italic> may promote cervical cancer and ovarian cancer <italic>via</italic> aberrant LIF signaling, which has been shown to regulate multiple hallmarks of cancer, including proliferation, metastasis and chemoresistance (<xref ref-type="bibr" rid="B69">Jones and Jenkins, 2018</xref>; <xref ref-type="bibr" rid="B70">Jorgensen and de la Puente, 2022</xref>). LIF also has a significant role in enriching and maintaining cancer stem cells, epithelial to mesenchymal transition, de-differentiation, and re-differentiation of cancer cells (<xref ref-type="bibr" rid="B53">Halder et&#xa0;al., 2022</xref>).</p>
</sec>
<sec id="s5">
<title>Conclusion remarks</title>
<p>In conclusion, available evidence supports a novel aspect of <italic>Ct</italic> pathogenesis controlled by the pleiotropic cytokine LIF (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4</bold>
</xref>). Despite the intended purpose of LIF production as a part of the host defense against intracellular <italic>Ct</italic> infection and host protective tissue healing, LIF-mediated signaling, particularly prolonged strong signaling, gradually transforms the microenvironment of the fallopian tube by diminishing the density of ciliated epithelial cells and increasing the population of less differentiated secretory epithelial cells. This harmful transformation of epithelium might be a key process leading to an enhanced risk of infertility, ectopic pregnancy and cancer.</p>
<fig id="f4" position="float">
<label>Figure&#xa0;4</label>
<caption>
<p>A potential role of LIF in <italic>Chlamydia</italic> pathogenesis. LIF is produced by epithelial cells upon <italic>Ct</italic> infection, which is required for maintaining epithelium homeostasis and normal tissue repair <italic>via</italic> autocrine LIF/LIFR signaling pathways. This would occur in many <italic>Ct-</italic>infected women without leaving serious complications. However, aberrant tissue repair is triggered by repeated or persistent infections, which results in marked reductions of ciliated epithelial cells and increases in secretory cells over time. The alteration in the cellular composition creates a microenvironment in fallopian tubes that may promote infertility, ectopic pregnancy and cancer.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-12-1029178-g004.tif"/>
</fig>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.</p>
</sec>
<sec id="s7" sec-type="funding-information">
<title>Funding</title>
<p>The study is supported by operating grant of the Canadian Institute of Health Research (CIHR) (Grant number: 201803PJT-159700) to JW. KW is supported by a Dalhousie Medical Research Foundation (DMRF) &#x2013; Infection, Immunity, Inflammation &amp; Vaccinology (I3V) Graduate Studentship.</p>
</sec>
<sec id="s8" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s9" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
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