The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Abstract

Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn’s disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2−/− mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2−/− mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.

SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling

“…While the present study focused on acute MDP-NOD2 signaling, chronic NOD2 activation has been implicated in the development of tolerance to bacterial PAMPs in intestinal macrophages 105 . Recent studies also highlight the physiological role of NOD2 signaling in non-immune cells 106,107 . Future studies will investigate how SLIT2 affects these aspects of NOD2 signaling.…”

The interplay between microbes and the immune response in inflammatory bowel disease

“…This correlates with our laboratory's recent finding that Nod2 −/− mice had delayed epithelial recovery and prolonged small intestinal mucosal damage following intraperitoneal injection of anti‐CD3ε monoclonal antibody (mAb) (Zanello et al . ). Conversely, we were unable to identify a difference in susceptibility to T cell transfer colitis using Nod2 −/− T cells (Zanello et al .…”

Immune Regulation of Intestinal Stem Cell Proliferation and Differentiation in Drosophila

“…We considered this an important question to address, as IMD pathway components are expressed and active in midgut progenitors (27)(28)(29), and germline-encoded immune pathways have critical homeostatic roles in the intestinal progenitor cells of other organisms. For example, mouse stem cells express the NOD2 and TLR4 bacterial sensors, and both receptors contribute to the regulation of stem cell viability (30)(31)(32)(33).…”

“…These observations have parallels in zebrafish, mice, and rats, where removal of the gut microbiome results in a decline in endocrine numbers (34,62,63), suggesting an evolutionarily conserved requirement for bacterial response pathways in the development of secretory cell lineages. Recent studies implicate the vertebrate sensor of cytosolic 23 PGN, NOD2, in epithelial regeneration (31,32), suggesting that immune-regulation of progenitor cell growth may be an evolutionarily conserved event. Our study does not determine if progenitor cell IMD regulates epithelial renewal by controlling progenitor viability, proliferation, or differentiation, and future experiments are required to address this question.…”