{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:52:10Z","timestamp":1753890730326,"version":"3.41.2"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Insulin-like peptide 5 (INSL5) is a peptide hormone with proposed actions in glucose homeostasis and appetite regulation <jats:italic>via<\/jats:italic> its cognate receptor, relaxin family peptide receptor 4 (RXFP4). Here, we look for evidence for their involvement in the immune system using a mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In silico analyses:<\/jats:italic> we queried public databases for evidence of expression of INSL5-RXFP4 in immune system tissues\/cells (NCBI\u2019s SRA and GeoProfiles) and disorders (EMBO-EBI) and performed phylogenetic footprinting to look for evidence that they are regulated by immune-associated transcription factors (TFs). <jats:italic>Experimental analyses:<\/jats:italic> We characterized the expression and correlation of INSL5\/RXFP4 and other immune system markers in central and peripheral immune organs from C57\/bl6 mice in seven cohorts. We tested whether fluctuations in circulating INSL5 induce an immune response, by injecting mice with 30 \u03bcg\/kg of INSL5 peptide in the peritoneum, and examining levels of immune markers and metabolic peptides in plasma. Lastly, we quantified the expression of <jats:italic>Rxfp4<\/jats:italic> in T-cells, dendritic cells and cell lines derived from human and mouse and tested the hypothesis that co-incubation of ANA-1 cells in INSL5 and LPS alters cytokine expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We find <jats:italic>Insl5<\/jats:italic> expression only in thymus (in addition to colon) where its expression was highly correlated with <jats:italic>Il-7<\/jats:italic>, a marker of thymocyte development. This result is consistent with our <jats:italic>in silico<\/jats:italic> findings that <jats:italic>Insl5<\/jats:italic> is highly expressed in thymic DP, DN thymocytes and cortical TEC\u2019s, and with evidence that it is regulated by thymocyte-associated TF\u2019s. We find <jats:italic>Rxfp4<\/jats:italic> expression in all immune organs, and moderately high levels in DCs, particularly splenic DCs, and evidence that it is regulated by immune-associated TF\u2019s, such as STAT\u2019s and GATA. <jats:italic>Systemic effects<\/jats:italic>: We observed significantly elevated concentrations of blood GLP-1, GIP, GCG and PYY following intraperitoneal injection of INSL5, and significantly altered expression of cytokines IL-5, IL-7, M-CSF, IL-15, IL-27 and MIP-2. <jats:italic>Immune cell effects<\/jats:italic>: Incubation of ANA-1 cells with INSL5 impeded cell growth and led to a transient elevation of IL-15 and sustained reduction in IL-1\u03b2, IL-6 and TNF\u03b1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We propose that INSL5-RXFP4 play a novel role in both central and peripheral immune cell signaling.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2020.610672","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T20:10:59Z","timestamp":1610655059000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Immune System Effects of Insulin-Like Peptide 5 in a Mouse 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