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The crosstalk between microbial sensors ELMO1 and NOD2 shape intestinal immune responses

Microbial sensors play an essential role in maintaining cellular homeostasis. Our knowledge is limited on how microbial sensing helps in differential immune response and its link to inflammatory diseases. Recently, we have shown that cytosolic sensor ELMO1 (Engulfment and Cell Motility Protein-1) binds to effectors from pathogenic bacteria and controls intestinal inflammation. Here, we show that ELMO1 interacts with another sensor, NOD2 (Nucleotide-binding oligomerization domain-containing protein 2), that recognizes bacterial cell wall component muramyl dipeptide (MDP). The polymorphism of NOD2 is linked to Crohn’s disease (CD) pathogenesis. Interestingly, we found that overexpression of ELMO1 and mutant NOD2 (L1007fs) were not able to clear the CD-associated adherent invasive E. coli (AIEC-LF82). To understand the interplay of microbial sensing of ELMO1-NOD2 in epithelial cells and macrophages, we used enteroid-derived monolayers (EDMs) from ELMO1 and NOD2 KO mice and ELMO1 and NOD2-depleted murine macrophage cell lines. The infection of murine EDMs with AIEC-LF82 showed higher bacterial load in ELMO1-KO, NOD2 KO EDMs, and ELMO1 KO EDMs treated with NOD2 inhibitors. The murine macrophage cells showed that the downregulation of ELMO1 and NOD2 is associated with impaired bacterial clearance that is linked to reduced pro-inflammatory cytokines and reactive oxygen species. Our results indicated that the crosstalk between microbial sensors in enteric infection and inflammatory diseases impacts the fate of the bacterial load and disease pathogenesis.