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Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease.sup.1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment.sup.3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2.sup.4,5, which increase the risk of stricturing.sup.6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14.sup.+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease--potentially as a complement to anti-TNF therapy. NOD2 deficiency drives fibrosis and stricturing complications in Crohn's disease through dysregulated homeostasis of activated fibroblasts and macrophages, which is ameliorated by gp130 blockade in human cell and zebrafish models., Author(s): Shikha Nayar [sup.1] [sup.2] , Joshua K. Morrison [sup.3] , Mamta Giri [sup.4] , Kyle Gettler [sup.1] [sup.4] , Ling-shiang Chuang [sup.1] , Laura A. Walker [sup.5] , Huaibin [...]