A myeloid-stromal niche and gp130 rescue in NOD2-induced Crohn’s disease

Crohn’s disease (CD) is a chronic inflammatory bowel disease, with frequent complications of aberrant scarring and narrowing. Crosstalk between activated and stromal myeloid cells is essential for pathogenicity^1.2 with an increase in intravasant monocytes correlated with the non-response to anti-TNF treatment³. The alleles at the highest risk of effect are loss of function NOD2^4.5 mutations, which increase the risk of stenosis⁶. However, the mechanisms underlying NOD2 pathogenicity and lifesaving pathways in anti-TNF refractory patients remain largely uncharacterized. Here, we show that the loss of NOD2 leads to homeostasis of activated fibroblasts and macrophages deregulated by ex vivo carrier patient analyzes NOD2 risk alleles. CD14 + PBMC from NOD2 carriers produce cells expressing high collagen, and an elevation of conserved signatures is observed in nod2-Zebrafish models deficient in intestinal lesions. Enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages led us to believe that blocking gp130 could save the activated program. We correlate the post-treatment induction of this pathway in anti-TNF non-responders and demonstrate in vivo improvement of the activated myeloid-stromal niche, using a specific inhibitor of gp130, bazedoxifene. Our results demonstrate new biological knowledge on fibrosis induced by NOD2 in CD; Blocking gp130 may be beneficial for some patients with CD, potentially complementing anti-TNF therapy.