In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 13, No. 603 ( 2021-07-21)
Abstract:
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 E 2 (PGE 2 ). PGE 2 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 (T H 1)/T H 17 infiltration and aggravated colitis development. PGE 2 administration ameliorated colitis in mouse models with defective PGE 2 production but not in animals with normal PGE 2 induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE 2 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 PGE 2 production.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.abb5071
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2021
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