Regulation of intestinal injury and enteric nervous system damage by enteric glia

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY: Gastrointestinal (GI) diseases, including inflammatory bowel disease (IBD) and bacterial infections, involve aberrant immune activation that results in tissue injury and prevents regeneration. However, therapies targeting inflammatory cytokines are not completely effective clinically and often lead to resistance and relapse. This highlights our incomplete understanding of the pathogenic mechanisms of GI diseases, particularly immune dysregulation. Increasing evidence suggests that the enteric nervous system (ENS) provides crucial signals to modulate mucosal immunity, subsequently limits tissue damage and promotes intestinal regeneration after injury. Within the ENS, glia outnumber neurons by nearly 5 fold. Despite originating from the Schwann cell lineage, enteric glia perform little myelination and, surprisingly, their role in intestinal injury remains largely unknown and controversial. Studies have demonstrated that enteric glia either protect epithelial integrity or have no significant impact in steady-state conditions. Furthermore, their involvement in intestinal pathogenesis and the underlying mechanisms remain largely unclear. Therefore, the causative role of enteric glia in GI diseases remains a major knowledge gap in mucosal biology. The overall goal of this study is to determine the pathogenic role of enteric glia in regulating intestinal injury. To address this, we analyzed single-cell dataset of IBD patients, generated novel transgenic mouse models to knockout specific signaling pathways in enteric glia, combined with different preclinical models of IBD and bacterial infection to induce acute intestinal injury. Our data show that 1) enteric glia undergo activation, also known as gliosis, upon intestinal injury; 2) TGF-β signaling controls enteric gliosis and subsequently exacerbates epithelial damage after injury; 3) Enteric gliosis recruits immune cells to the muscularis propria via Vcam1; 4) Glial Vcam1 ablation protects against intestinal dysmotility. These findings demonstrate that enteric glia play an active role in regulating two key aspects of intestinal injury—epithelial damage and dysmotility. In this proposed study, we will further determine 1) the mechanism by which TGF-β-dependent enteric gliosis exaggerates epithelial damage (K99); 2) the causal role of glia-recruited myeloid cells in attacking the ENS and resulting in intestinal dysmotility (K99); and 3) the role of activity-dependent gliotransmission in exacerbating intestinal injury (R00). Successful completion of this proposed study will elucidate the immunoregulatory role of enteric glia during intestinal injury, advancing our current understanding of ENS—mucosal immunity interactions. The principal investigator is a full-time postdoctoral associate at Yale School of Medicine, with a PhD and post- doctoral training in neuroimmunology and mucosal immunology. His career goal is to become an independent investigator studying glia-immune interactions in GI diseases. The proposed K99 phase training plan will provide the candidate with the mentorship and coursework to develop the necessary expertise to execute the proposed project and become independent in the field of enteric glia and GI diseases during R00 phase.