LECT2 (leucocyte cell-derived chemotaxin 2) is a hormone-like protein that was originally identified as a chemokine mediating neutrophil migration (1). Subsequently, it has also been defined as chondromodulin II (CHM2 or ChM-II) due to its function in promoting chondrocyte proteoglycan synthesis and cartilage growth (2). In fact, as a member of chondromodulin family, although CHM2 shares lower sequence similarity with its family member CHM-1, both of them function as anti-angiogenic factors (3, 4). CHM2 suppresses angiogenesis by blocking VEGF165-VEGFR2 signaling in liver cancer (5) and reduces endothelial cell migration and tube formations by activating LECT2-Tie1 signaling in liver fibrosis (6).

LECT2 is also identified as a hepatokine. Hepatocyte-derived LECT2 not only regulates hepatocyte cells in an autocrine mode, but can also be secreted into the bloodstream to act on cells of other tissues in a paracrine way to modulate multiple metabolic homeostasis or disorders such as glucose metabolism, non-alcoholic fatty liver disease (NAFLD) (7, 8), alcohol-induced liver cirrhosis (9), obesity (10), diabetes (11, 12), and atherosclerosis (13). LECT2 is also positively correlated with diet-induced weight cycling in mice and humans, suggesting that LECT2 is a sensing hepatokine for nutritional regulation-mediated metabolic homeostasis and functions as an indicator for management of obesity in the clinic (14, 15).

Besides its soluble functioning as a cytokine or hepatokine, LECT2 also exists in the form of amyloidosis (aLECT2) and is involved in renal and hepatic amyloid lesions (16–18). aLECT2 has been found to deposit in vessels, interstitial, and glomeruli of renal biopsies (19–21). The mutation or genetic variations of LECT2 are responsible for the formation of aLECT2, while the misfolding LECT2, which leads to insoluble fibrils aggregated in cells and tissues, might be the potential pathogenesis of LECT2-mediated amyloidosis (19, 20). However, the specific role of aLECT2 in amyloidosis is still unclear, and there is also a disputation about whether this protein is feasible as a diagnosis and treatment for aLECT2-mediated amyloidosis.

Furthermore, more recent research has revealed the link between LECT2 and the development of multiple immunological diseases such as sepsis (22–24), atherosclerosis (13, 25–27), osteoporosis (28, 29), arthritis (30–33), diabetes (10–12, 34), atopic dermatitis (35), and non-alcoholic steatohepatitis (NASH) (7, 8). Nonetheless, it is disease-dependent for the action mechanisms and signaling of LECT2. Thus, herein, we have analyzed the expression and roles of LECT2 and its ligand proteins in various inflammatory diseases to provide a comprehensive review that will help researchers examining these processes and determining the bioavailability of LECT2 in the future.

The human LECT2 gene is located at chromosome 5q31.1–32 and consists of three introns and four exons (36). Its cDNA is 456 nucleotides (nts) in length, containing an open reading frame encoding a polypeptide of 151 amino acid (aa) residues with a calculated molecular weight of 16.39 kDa and a isoelectric point of 9.42 (36). The LECT2 protein is the only member of the zinc-dependent metalloendopeptidases M23 family in vertebrates, which contains a zinc ion as a cofactor and prefers peptides containing polyglycine residues (37, 38). The phylogenic analysis shows that LECT2 is highly conserved from teleosts to Mammalia ( Figure 1A ). All of them have a signal peptide, three conserved disulfide bonds, and three metal-binding sites ( Figure 1B ). These conserved sequences or sites are crucial for the functioning of LECT2, and they also provide the theoretical basis to explore the functions of LECT2 by comparative biology.

LECT2 is primarily produced in hepatocytes and mainly secreted to the bloodstream (16), but it is also found in other tissues or cells, such as macrophages (8, 13), parathyroid cells (39), adipocytes (10, 40), cerebral nerve cells (39), and vascular endothelial cells (6, 26).

LECT2 exhibits its pleiotropic functions via its receptors, including CD209 antigen-like protein A (CD209a) (22, 41), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie1) (6), MET (tyrosine protein kinase Met, also called c‐Met) (37, 42, 43), L1 cell adhesion molecule (L1CAM or SAX-7) (44), MNR-1 (44), and transferrin (Trf) (45) ( Figure 2 ). CD209a is the first identified LECT2 receptor discovered by our group (41), and it contributes to enhancing the bacterial clearance ability of macrophages by phosphorylating the c-Jun N-terminal kinase (JNC) ( Figure 2A ) (22, 41). c-Met is the other receptor of LECT2, and the c-Met-LECT2 protein–protein interaction (PPI) impedes MET receptor activation to inhibit vascular invasion, metastasis, proliferation, and stemness of several cancers by antagonizing different cancer activation pathways ( Figure 2B ) (43, 46–48). In addition, Shirasaki et al. found that LECT2 functions as an anti-viral protein against lymphocytic choriomeningitis virus (LCMV) by binding to c-Met and thus competes with HGF-MET signaling ( Figure 2B ) (42). Tie1, a well-known angiopoietin receptor in many angiogenesis-related physiological and pathological processes (49), was also found to interact with LECT2. LECT2 promotes the dissociation of Tie1-Tie2 heterodimerization and the formation of Tie1-Tie2 homodimerization, which surpasses the invasion and metastasis of endothelial cells by activating PARP signaling ( Figure 2E ) (6). In Caenorhabditis elegans, muscle-secreted LECT-2 is an orthologue of vertebrate LECT2. It forms a multiprotein receptor–ligand complex with two skin transmembrane ligands, L1CAM and MNR-1, and a neuronal transmembrane receptor, DMA-1, which guides the growth of dendritic terminal branches ( Figure 2D ) (44). Trf is a glycoprotein with iron-binding and anti-microbial activity in vertebrates ( Figure 2C ) (50). Our group revealed that LECT2 interacts with Trf, and this interaction is highly conserved from fish to mouse (45).

In its structure, LECT2 has high similarity among different vertebrates, indicated by their high conservation of three disulfide bonds and three metal-binding sites. The homology of LECT2 between different species provides the possibility to study its functions using comparative immunological methods. Currently, two of the five reported ligand proteins (CD209a and Trf) of LECT2 were firstly identified by our group in teleosts using the yeast two-hybrid system (45, 64), and the two interactions were further verified by our and the other groups. The LECT2-CD209a interaction was found to mediate bacterial clearance and obesity and drive the expansion and mobility of HSCs by modulating the macrophages and osteolineage cells (41). For LECT2-Trf interaction, although this protein–protein interaction (PPI) exists from teleosts to mice (45), its specific pathophysiologic functions are still unknown. Additionally, the complex assembled by LECT2, L1CAM, MNR-1, and DMA-1 is indispensable for the growth of dendritic terminal branches in C. elegans (44). Although all the homologous components of this complex are present in vertebrates, whether this complex exists in vertebrates and its potential roles remain unknown. These discoveries of LECT2 receptors further verify the feasibility of the digesting functions of novel proteins by comparative immunology.

Mounting evidence supports that LECT2 has versatile roles in immune diseases. It attenuates tumorigenesis by modulating TIM (51, 52); modulates inflammatory responses in several tissues such as liver (7, 8, 25, 40, 56, 59), bone marrow (29), joints (30–33), and blood vessels (13, 25–27); alleviates bacteria/virus-induced sepsis (22, 23, 42, 67–71); and accelerates the progression of allergic diseases (35, 77). It also mediates the Wnt/β-catenin pathway to regulate osteogenic differentiation of MSCs (28). The interaction of LECT2 with CD209a promotes the proliferation of HSCs in the bone marrow and mobilization to the blood, and it also regulates HSC homeostasis by affecting the expression of TNFα in macrophages and osteoblasts (41). Given the multifunctionality of LECT2 and its theranostical application in multiple immune-related diseases, there are many areas that are worth further investigating. Firstly, many of the LECT2-mediated pathophysiologic roles interplay with each other, and it is imperative to investigate whether and how LECT2 modulates the crosstalk among different immune diseases. For example, LECT2 is involved in the development of several liver immune diseases such as NAFLD, insulin resistance, liver regeneration, and HCC. LECT2 is the common mediator for them, and these liver immune diseases can be interchangeable or occur simultaneously. However, no related literature describes the role of LECT2 in their crosstalk. Secondly, considering the broad spectrum of LECT2-mediated liver immune diseases, it is theoretically feasible to construct an algorithm using LECT2 levels to predicate the progression of these diseases. Thirdly, LECT2 has been found to promote the progress of several immune diseases and is considered as a therapeutic target, but no agent with activity that reduces LECT2 levels has been identified for the moment. Further studies are needed to screen/identify agents with functions that lower LECT2 levels. Finally, the potentially clinical applications of LECT2 in immune diseases have been verified in a mouse model. However, further study is still imperative to shed light on their action mechanisms to avoid unpredicted risks before LECT2 is used clinically in humans. For example, recombinant LECT2 (rLECT2) administration was found to alleviate the sepsis induced by bacteria and virus in a mouse model, and LECT2 is also negatively associated with sepsis in humans, but there is a dearth of studies about whether LECT2 has similar mechanisms and efficacy. Therefore, there remains a need for studies focusing on the action mechanism and clinical applications of rLECT2 in humans. Further exploration of the role of LECT2 in varieties of immune diseases and its correlation with clinical immune-related diseases will advance the development of LECT2 as an appealing theranostical target for immune diseases.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.