Linking the Endocrine System with Immunity

Dorota Latek^1*Yildiz Tutuncu²

• ¹Univeristy of Warsaw, Faculty of Chemistry, Warsaw, Poland
• ²Division of Medical Biology, School of Medicine, Koc University, Istanbul, Türkiye

It has been known that diabetes elevates the HPA axis acKvity causing increased release of ACTH sKmulaKng the adrenal gland for glucocorKcoid producKon, but the molecular mechanisms underlying this steroidogenesis are sKll not fully understood. Magalhães et al. [2] invesKgated the effects of TLR4 pathway acKvaKon via lipopolysaccharide (LPS) derived from intesKnal bacteria on adrenal steroidogenesis in diabeKc mice. Experiments with TLR4 antagonist (TAK-242) and an alloxan-induced diabetes mouse model, first described in 1943 by Shaw Dunn and McLetchie as alloxan-induced damaging of b-cells in rats [3], showed that corKcosterone levels were significantly reduced. The findings suggest that TLR4 acKvaKon by bacterial LPS contributes to adrenal steroidogenesis in diabetes and may serve as a novel target for managing glucocorKcoid-related complicaKons.Only 20 stem cell-like CD8+ T cells inducing type 1 diabetes (T1D) in healthy mice [4] and modulated self-reacKve CD8+ T cells used to revert it are menKoned by Yang et al. [5], as the hallmark of T1D pathophysiology is known to be the autoanKgen-driven T-cell clonal amplificaKon. Stem cell-like progenitor CD8+ T cells in the pLN replenish the short-lived populaKon of pathogenic T cells that directly destroy β-cells and cause T1D [4]. PrevenKon and treatment of T1D by restoring or inducing immune tolerance to β-cells requires a precise descripKon of mechanisms underlying state changes of CD8+ T cells. Among new T1D therapies, enhancing the exhausted CD8+ T cell reacKvity, CRISPR/Cas9-based gene ediKng in CD8+ T cells, CAR-T engineering of T cells, and T cell differenKaKon by single-cell RNA sequencing or single-cell transcriptome analysis combined with T cell receptor sequencing are described. Yang et al. emphasize that the best therapy for T1D is to regulate the autoimmune T cell response while maintaining the proper immune system response to foreign anKgen invasion and avoiding the systemic immunosuppression.Any risk associated with gestaKon negaKvely affects the steadily declining birth rate in Europe (3.67 million births in 2023 with almost half of children born to first-Kme mothers). GestaKonal diabetes mellitus imposes a significant but differenKal risk in certain regions and Ray et al. [6] discuss its geneKc, gene-environment, and inflammatory causes describing SLC30A8, CDKAL1, TCF7L2, IRS1, GCK geneKc variants and NF-κB, TNF-a, and IL-6 inflammatory pathways.The unique, lipopolysaccharide-induced, chronic inflammaKon mouse model, with implicaKons for dissecKng the impact of endotoxemia on reproducKon, was demonstrated by Garcia et al. [7]. EssenKal for reproducKon, luteinizing and follicle-sKmulaKng hormone levels were elevated upon LPS-mediated sKmulaKon of the toll-like receptor 4 signaling cascade, leading to paracrine acKvaKon of TGF-β pathways. Furthermore, RNA-sequencing revealed LPS-induced changes in the pituitary indicaKng local paracrine mechanisms for FSH upregulaKon with TGBβ2 as an important factor. However, transcripts for LH and FSH decreased or were not changed suggesKng the secreKon of these gonadotropins independent of transcripKon but rather induced by the pituitary microenvironment signaling. Garcia et al. discuss their results obtained with chronic, 6-week, low-dose LPS sKmulaKon with previous contradicKng studies showing suppression of the HPG axis with high-dose and acute LPS.The complex nature of signaling crosstalk leading to open contradictory or unconvincing conclusions is raised in another arKcle. Rahman et al. [8] discuss complicaKons that can be introduced with the Cre-Lox system in knockout mouse models. They compared two KO mouse models, Lyz2Cre and Nod1 floxed, and observed that myeloid Cre expression alone was enough to induce an anK-inflammatory phenotype protecKng against palmitate-induced glucose intolerance. Notably, Lyz2Cre reduced absolute insulin secreKon, increased insulin clearance, and increased insulin sensiKvity in the absence of palmitate infusion. What is more, Lyz2Cre expression impaired bone marrow-derived macrophage funcKon. Rahman et al. suggest that these observed effects could be due to Cre toxicity, haploinsufficiency of the Lys2 locus, or some effect of non-specific expression of Cre in disKnct locaKons and emphasize the role of appropriate controls while using the Lyz2Cre model.Autoimmune diseases open occur with comorbidiKes of either autoimmune origins such as Sjögren's syndrome or non-autoimmune pathophysiology such as cardiovascular or kidney diseases. Hyperuricemia is known as the pathological basis of gout, an inflammatory joint disease, and can lead to the occurrence and progression of hypertension, diabetes, chronic kidney disease, and cardiovascular diseases, etc. Zhang et al. [9] reported that paKents with increased inflammaKon response index (SIRI) and systemic immune-inflammaKon index (SII), integraKng three independent white blood cell subsets and platelets, also had elevated hyperuricemia risk with increased BMI as a mediaKng effect. Another linkage between different types of autoimmune diseases is discussed by Wu et al. [10] on the example of hypothyroidism and the resulKng reduced risk of inflammatory bowel disease, specifically Crohn's disease.One of the most prevalent autoimmune diseases affecKng an endocrine gland are hypothyroidism (Hashimoto's disease) and hyperthyroidism (Graves' disease). The link between these thyroid diseases causing chronic inflammaKon and thyroid cancers, though observed, is not clear and requires extensive studies. A rare case of a collision tumor of a thyroid has been detected by Zhang et al. [11] in a 64-yearold paKent. This rare coexisKng of primary thyroid MALT lymphoma and papillary thyroid cancer has been treated with a total thyroidectomy along with lymphadenectomy of the central compartment without any further signs of metastasis or tumor recurrence. Hashimoto's thyroidiKs is associated with both, MALT and PTC lymphoma. However, MALT lymphoma is less prevalent in the thyroid and more frequent in the stomach being open caused by Helicobacter pylori-induced chronic inflammaKon. This Research Topic describes well-known associaKons between immune and endocrine systems in detail but also shows seemingly contradictory cases uncovering the hidden hormone regulaKon and signaling crosstalk. Understanding the linkage between these two systems is however necessary to propose new therapeuKc strategies.