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Sympathetic nerves regulate intestinal regeneration through IL22 signaling

ABSTRACT: The intestine is a barrier tissue whose epithelium has high intrinsic turnover rate; intestinal stem cells, in response to signals from the niche, self-renew and produce progeny that differentiate to fulfill the continuous demand for new epithelial cells that are continuously shed into the lumen. The intestine is innervated by a dense network of peripheral nerves that controls nutrient absorption, intestinal motility, and visceral pain sensation. However, the roles of neurons in regulating epithelial cell homeostasis or regeneration remain as yet undiscovered. Here we investigate the effects of gut-innervating sympathetic neurons on epithelial cell repair following irradiation (IR)-induced gut injury. We observed that sympathetic innervation density in the gut increases post IR, while chemical sympathetic denervation impairs gut regeneration. Combining single cell RNA-sequencing and in vivo experiments, we discovered that sympathetic neurons regulate gut regeneration through modulation of IL22 production in type 3 innate lymphoid cells (ILC3) downstream of 2-adrenergic receptor signaling. These results define a novel neuroimmune axis important for intestinal regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE214821 | GEO | 2023/08/18

REPOSITORIES: GEO

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Project description:The Interleukin-22 (IL22) pathway plays a key role in maintaining homeostasis at the mucosal surfaces and is frequently dysregulated during infectious and inflammatory diseases. Human genome-wide association studies performed at the WTSI have identified SNPs in and around the human IL-22 gene that are associated with IBD susceptibility. The IL-22 cytokine is produced by cells of the innate and adaptive immune systems within the intestinal mucosa and acts on the IL-22 receptor (IL-22RA1) that is present specifically on intestinal epithelial cells. Studies to date have shown the that IL-22 pathway is linked to proliferative and anti-apoptotic pathways, as well as anti-microbial molecule production that help control bacterial invasion and prevent tissue damage. We are characterizing a novel IL-22RA1 KO mouse and have shown that these mice are highly susceptible to enteric bacterial pathogens, such as Citrobacter rodentium and Clostridium difficile. However, the mechanism of this protective immunity is poorly understood. The aim of this project is to identify novel molecules or pathways downstream of IL-22 signaling that provide the mechanistic link between IL-22RA1 and innate immunity. To maintain mouse colonic epithelial cells in vitro, we used an organoid culture system that faithfully recapitulates the crypt architecture of the gastrointestinal epithelium. Primary colonic epithelial crypts were isolated from age-matched wildtype and IL-22ra1 knock-out mice (n = 4 per genotype), and subsequently cultured in the presence of defined growth factors and Matrigel for 5 days. The resulting mature organoids were then either treated with Control medium (Advanced DMEM/F12) or mouse recombinant IL-22 (50ng/ml) for 16 hours. Total RNA were extracted using the QIAgen RNeasy Micro Kit, including an on-column DNAse digestion step, according to manufacturer's protocol. We are submit total RNA samples of good quality (RIN > 7) and quantity.The culture and stimulation conditions have been optimised to achieve significant and specific induction of known target genes such as the antimicrobial peptides RegIIIb, RegIIIg, S100a8 and S100a9. Two technical replicates will be available for each genotype x condition. We aim to sequence 5GBp per replicate, and 5 replicates per lane on an Illumina platform. Through this dataset, we hope to discover epithelial cell-specific pathways downstream of IL-22 signaling that are ablated in the absence of its receptor.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

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Sympathetic nerves regulate intestinal regeneration through IL22 signaling

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