Immune System Effects of Insulin-Like Peptide 5 in a Mouse Model

Vahkal, Brett; Yegorov, Sergey; Onyilagha, Chukwunonso; Donner, Jacqueline; Reddick, Dean; Shrivastav, Anuraag; Uzonna, Jude E.; Good, Sara V.

doi:10.3389/fendo.2020.610672

Cited by 6 publications

(7 citation statements)

References 52 publications

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“…Amongst gut endocrine cell products, insulin-like peptide 5 (INSL5) is confined to the distal large intestine, where it occurs in L-type enteroendocrine cells (EEC) that also contain glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), both of these being costored with INSL5 in the same secretory vesicles of these EEC (Grosse et al 2014 ; Billing et al 2018 ; Vahkal et al 2021 ). The administration of an INSL5 mimetic and stimulation of hormone release from colonic L-cells using DREADD technology both cause defecation, but there is no evidence that either GLP-1 or PYY is involved in defecation control (Diwakarla et al 2020 ; Lewis et al 2020 ; Pustovit et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine

et al. 2022

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The gastrointestinal hormone, insulin-like peptide 5 (INSL5), is found in large intestinal enteroendocrine cells (EEC). One of its functions is to stimulate nerve circuits that increase propulsive activity of the colon through its receptor, the relaxin family peptide 4 receptor (RXFP4). To investigate the mechanisms that link INSL5 to stimulation of propulsion, we have determined the localisation of cells expressing Rxfp4 in the mouse colon, using a reporter mouse to locate cells expressing the gene. The fluorescent signal indicating the location of Rxfp4 expression was in EEC, the greatest overlap of Rxfp4-dependent labelling being with cells containing 5-HT. In fact, > 90% of 5-HT cells were positive for Rxfp4 labelling. A small proportion of cells with Rxfp4-dependent labelling was 5-HT-negative, 11–15% in the distal colon and rectum, and 35% in the proximal colon. Of these, some were identified as L-cells by immunoreactivity for oxyntomodulin. Rxfp4-dependent fluorescence was also found in a sparse population of nerve endings, where it was colocalised with CGRP. We used the RXFP4 agonist, INSL5-A13, to activate the receptor and probe the role of the 5-HT cells in which it is expressed. INSL5-A13 administered by i.p. injection to conscious mice caused an increase in colorectal propulsion that was antagonised by the 5-HT3 receptor blocker, alosetron, also given i.p. We conclude that stimuli that excite INSL5-containing colonic L-cells release INSL5 that, through RXFP4, excites 5-HT release from neighbouring endocrine cells, which in turn acts on 5-HT3 receptors of enteric sensory neurons to elicit propulsive reflexes.

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Section: Introductionmentioning

confidence: 99%

Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine

et al. 2022

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“…As far as we know, they have never been reported to be directly related to CAD before, but some have been confirmed to affect the changes of immune targets in circulation. For example, INSL5, as a peptide hormone, after intraperitoneal injection, leads to significant changes in inflammatory factors such as IL-5, IL-7, M-CSF, IL-15 and IL-27 [ 43 ], and these inflammatory signals typically play a regulatory role in CAD. However, more direct evidence is needed to explore the causal relationship between them and CAD.…”

Section: Discussionmentioning

confidence: 99%

Identification of diagnostic biomarkers and therapeutic targets in peripheral immune landscape from coronary artery disease

Feng

Zhang

et al. 2022

J Transl Med

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Background Peripheral biomarkers are increasingly vital non-invasive methods for monitoring coronary artery disease (CAD) progression. Their superiority in early detection, prognosis evaluation and classified diagnosis is becoming irreplaceable. Nevertheless, they are still less explored. This study aimed to determine and validate the diagnostic and therapeutic values of differentially expressed immune-related genes (DE-IRGs) in CAD. Methods We downloaded clinical information and RNA sequence data from the GEO database. We used R software, GO, KEGG and Cytoscape to analyze and visualize the data. A LASSO method was conducted to identify key genes for diagnostic model construction. The ssGSEA analysis was used to investigate the differential immune cell infiltration. Besides, we constructed CAD mouse model (low-density lipoprotein receptor deficient mice with high fat diet) to discover the correlation between the screened genes and severe CAD progress. We further uncovered the role of IL13RA1 might play in atherosclerosis. Results A total of 762 differential genes were identified between the peripheral blood of 218 controls and 199 CAD patients, which were significantly associated with infection, immune response and neural activity. 58 DE-IRGs were obtained by overlapping the differentially expressed genes(DEGs) and immune-related genes downloaded from ImmpDb database. Through LASSO regression, CCR9, CER1, CSF2, IL13RA1, INSL5, MBL2, MMP9, MSR1, NTS, TNFRSF19, CXCL2, HTR3C, IL1A, and NR4A2 were distinguished as peripheral biomarkers of CAD with eligible diagnostic capabilities in the training set (AUC = 0.968) and test set (AUC = 0.859). The ssGSEA analysis showed that the peripheral immune cells had characteristic distribution in CAD and also close relationship with specific DE-IRGs. RT-qPCR test showed that CCR9, CSF2, IL13RA1, and NTS had a significant correlation with LDLR−/− mice. IL13RA1 knocked down in RAW264.7 cell lines decreased SCARB1 and ox-LDL-stimulated CD36 mRNA expression, TGF-β, VEGF-C and α-SMA protein levels and increased the production of IL-6, with downregulation of JAK1/STAT3 signal pathway. Conclusions We constructed a diagnostic model of advanced-stage CAD based on the screened 14 DE-IRGs. We verified 4 genes of them to have a strong correlation with CAD, and IL13RA1 might participate in the inflammation, fibrosis, and cholesterol efflux process of atherosclerosis by regulating JAK1/STAT3 pathway.

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“…The expression of Insl5 and Rxfp4 mRNA has been detected in the pancreas, thymus and in the gastrointestinal tract, 202,291 particularly in the L‐cells of distal gut 292–294 ; INSL5 has been shown to function as an orexigenic hormone, 291 and to influence colonic propulsion, 232,295 immune cell function, 296 and even human sperm motility 297 . Finally, a recent study identified a potential role for INSL5 (or relaxin‐3) signaling via ventral hypothalamic RXFP4 in the control of high‐fat and high‐protein diet consumption in mice 298 .…”

Section: Insulin‐like (Relaxin)‐family Peptide and Receptor Systemsmentioning

confidence: 99%

History of key regulatory peptide systems and perspectives for future research

Chen

Rehfeld

Watts

et al. 2023

J Neuroendocrinology

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Throughout the 20th Century, regulatory peptide discovery advanced from the identification of gut hormones to the extraction and characterization of hypothalamic hypophysiotropic factors, and to the isolation and cloning of multiple brain neuropeptides. These discoveries were followed by the discovery of G‐protein‐coupled and other membrane receptors for these peptides. Subsequently, the systems physiology associated with some of these multiple regulatory peptides and receptors has been comprehensively elucidated and has led to improved therapeutics and diagnostics and their approval by the US Food and Drug Administration. In light of this wealth of information and further potential, it is truly a time of renaissance for regulatory peptides. In this perspective, we review what we have learned from the pioneers in exemplified fields of gut peptides, such as cholecystokinin, enterochromaffin‐like‐cell peptides, and glucagon, from the trailblazing studies on the key stress hormone, corticotropin‐releasing factor, as well as from more recently characterized relaxin‐family peptides and receptors. The historical viewpoints are based on our understanding of these topics in light of the earliest phases of research and on subsequent studies and the evolution of knowledge, aiming to sharpen our vision of the current state‐of‐the‐art and those studies that should be prioritized in the future.

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Immune System Effects of Insulin-Like Peptide 5 in a Mouse Model

Cited by 6 publications

References 52 publications

Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine

Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine

Identification of diagnostic biomarkers and therapeutic targets in peripheral immune landscape from coronary artery disease

History of key regulatory peptide systems and perspectives for future research

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