Abstract
Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3−/−) were generated. Gab2/3−/− mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3−/− hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3−/− mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis.
Highlights
The healthy gut has strong mechanisms in place to promote tolerance and control inflammation in response to environmental triggers such as infection and bacterial products
As early as 8 weeks of age, rectal prolapse was observed in Grb2associated binding protein 2 (Gab2)/3−/− mice and approximately 1/3 of the mice developed rectal prolapse (50/136) compared to none detected in control mice as determined during a representative 15-month observation period
The results revealed previously unappreciated negative regulatory roles in prevention of spontaneous colitis and suppression of Dextran Sodium Sulfate (DSS)-induced colitis
Summary
The healthy gut has strong mechanisms in place to promote tolerance and control inflammation in response to environmental triggers such as infection and bacterial products. When this inflammation is not resolved, chronic uncontrolled inflammation of the intestine results in inflammatory bowel disease (IBD) [1]. Crohn’s disease affects the small intestine and colon, typically involving transmural inflammation, ulceration, and fistulae. Human IBD is a complex disorder resulting from the combination of genetic predisposition, environmental triggers, and the loss of integrity of the mucosal immune system. The genetic susceptibility is higher in Crohn’s disease than in ulcerative
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