Department of Biology, University of Winnipeg, Winnipeg, MB, Canada.
Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.
Front Endocrinol (Lausanne). 2021 Jan 14;11:610672. doi: 10.3389/fendo.2020.610672. eCollection 2020.
Insulin-like peptide 5 (INSL5) is a peptide hormone with proposed actions in glucose homeostasis and appetite regulation 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.
we queried public databases for evidence of expression of INSL5-RXFP4 in immune system tissues/cells (NCBI's 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). 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 μg/kg of INSL5 peptide in the peritoneum, and examining levels of immune markers and metabolic peptides in plasma. Lastly, we quantified the expression of 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.
We find expression only in thymus (in addition to colon) where its expression was highly correlated with , a marker of thymocyte development. This result is consistent with our findings that is highly expressed in thymic DP, DN thymocytes and cortical TEC's, and with evidence that it is regulated by thymocyte-associated TF's. We find expression in all immune organs, and moderately high levels in DCs, particularly splenic DCs, and evidence that it is regulated by immune-associated TF's, such as STAT's and GATA. : 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. : Incubation of ANA-1 cells with INSL5 impeded cell growth and led to a transient elevation of IL-15 and sustained reduction in IL-1β, IL-6 and TNFα.
We propose that INSL5-RXFP4 play a novel role in both central and peripheral immune cell signaling.
胰岛素样肽 5（INSL5）是一种肽类激素，据推测其在葡萄糖稳态和食欲调节中发挥作用，其同源受体为松弛素家族肽受体 4（RXFP4）。在这里，我们使用小鼠模型寻找其参与免疫系统的证据。
我们在公共数据库中查询 INSL5-RXFP4 在免疫系统组织/细胞中的表达证据（NCBI 的 SRA 和 GeoProfiles）和疾病（EMBO-EBI），并进行系统发育足迹分析，以寻找它们受免疫相关转录因子（TFs）调节的证据。我们描述了 C57/bl6 小鼠七个队列的中央和外周免疫器官中 INSL5/RXFP4 和其他免疫标志物的表达和相关性。我们通过向腹膜内注射 30μg/kg 的 INSL5 肽来测试循环 INSL5 波动是否会引起免疫反应，并检查血浆中免疫标志物和代谢肽的水平。最后，我们量化了 T 细胞、树突状细胞和源自人和小鼠的细胞系中的 表达，并测试了 ANA-1 细胞共孵育 INSL5 和 LPS 是否改变细胞因子表达的假设。
我们仅在胸腺（除结肠外）中发现 表达，其表达与胸腺细胞发育标志物 高度相关。这一结果与我们的研究结果一致，即 高度表达于胸腺 DP、DN 胸腺细胞和皮质 TEC，并证明其受胸腺细胞相关 TF 的调节。我们在所有免疫器官中都发现了 表达，在 DC 中表达水平较高，特别是脾 DC，并且有证据表明它受免疫相关 TF（如 STAT 和 GATA）调节。我们观察到腹腔内注射 INSL5 后血液 GLP-1、GIP、GCG 和 PYY 浓度显著升高，细胞因子 IL-5、IL-7、M-CSF、IL-15、IL-27 和 MIP-2 的表达显著改变。我们发现，与 INSL5 孵育可阻碍 ANA-1 细胞的生长，并导致短暂的 IL-15 升高和持续的 IL-1β、IL-6 和 TNFα减少。
我们提出 INSL5-RXFP4 在中枢和外周免疫细胞信号传导中发挥新的作用。
