A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice

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Science Translational Medicine  21 Jul 2021:
Vol. 13, Issue 603, eabb5071
DOI: 10.1126/scitranslmed.abb5071

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Leveraging stromal cells

Reducing the activation of proinflammatory signaling pathways has been shown to have therapeutic effects in animal models and in patients with inflammatory bowel disease (IBD). However, a substantial proportion of patients do not respond to available therapies. Here, Gao et al. investigated the endogenous immune mechanisms activated in IBD to identify potential therapeutic targets. The authors identified a population of stromal cells marked by Twist2 that suppresses inflammation in animal models of IBD by producing and suppressing inflammatory M1 macrophage polarization. In patients, they identified an inverse correlation between severity of disease and stromal cell Cox2 expression. Targeting this endogenous signaling might be an effective strategy to reduce inflammation in IBD.


Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E2 (PGE2). PGE2 induction requires a nuclear factor κB–independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (TH1)/TH17 infiltration and aggravated colitis development. PGE2 administration ameliorated colitis in mouse models with defective PGE2 production but not in animals with normal PGE2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE2 biosynthesis, in inflamed tissues, and especially in colon Vimentin+Twist2+ stromal cells, in about 60% of patients with active Crohn’s disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE2 production.

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