Protective role of tumor necrosis factor (TNF) receptors in chronic intestinal inflammation: TNFR1 ablation boosts systemic inflammatory response

Abstract

Tumor necrosis factor-a (TNF-a) acts as a key factor for the development of inflammatory bowel diseases (IBDs), whose function is known to be mediated by TNF receptor 1 (TNFR1) or TNFR2. However, the precise role of the two receptors in IBD remains poorly understood. Herein, chronic colitis was established by oral administration of dextran sulfate sodium (DSS) in TNFR1 or TNFR2 À / À mice. Unexpectedly, TNFR1 or TNFR2 deficiency led to exacerbation of signs of colitis compared with wild-type (WT) counterparts. Of note, TNFR1 ablation rendered significantly increased mortality compared with TNFR2 and WT mice after DSS. Aggravated pathology of colitis in TNFR1 À / À or TNFR2 À / À mice correlated with elevated colonic expression of proinflammatory cytokines and chemokines. Importantly, ablation of TNFR1 or TNFR2 increased apoptosis of colonic epithelial cells, which might be due to the heightened ratio of Bax/Bcl-2 and increased expression of caspase-8. Intriguingly, despite comparable intensity of intestinal inflammation in TNFR-deficient mice after DSS, systemic inflammatory response (including splenomegaly and myeloid expansion) was augmented dramatically in TNFR1 À / À mice, instead of TNFR2 À / À mice. Granulocyte macrophage colony-stimulating factor (GMCSF) was identified as a key mediator in this process, as neutralization of GMCSF dampened peripheral inflammatory reaction and reduced mortality in TNFR1 À / À mice. These data suggest that signaling via TNFR1 or TNFR2 has a protective role in chronic intestinal inflammation, and that lacking TNFR1 augments systemic inflammatory response in GMCSF-dependent manner.

A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-cis-12-octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40-MEK-ERK Pathway

“…TNFR2 signaling mediates the activation of MLCK and the change in localization of occludin. TNFR2 signaling also induces infiltration of macrophages and neutrophils into the lamina propria and activates Th17 cells (50,51). Su et al (20) reported that the induced expression of TNFR2 in murine colitis promoted apoptosis of intestinal epithelial cells, chemokine overexpression, and exacerbation of inflammation.…”

Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice

“…While some of the epidemiological studies did observe sexually dimorphic effects, other studies did not [72]. Interestingly however, several of the identified sexually dimorphic genes containing a function in inflammatory processes have previously been linked to IBD including Ccr3 [73], Ccl11 [74], Ncf1 [75] and Tnfr [76]. Apart from genes playing a role in immune response and inflammation, we identified cancer-relevant genes in the colon showing sex-differential expression using IPA.…”

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

“…A study using a colitis mouse model suggests that both TNFR1 and TNFR2 have protective functions in intestinal inflammation[31]. Herein, intestinal inflammation was provoked by oral application of dextran sulfate in mice deficient for TNFR1 or TNFR2 as well as wildtype controls.…”

“…Herein, intestinal inflammation was provoked by oral application of dextran sulfate in mice deficient for TNFR1 or TNFR2 as well as wildtype controls. TNFR1 or TNFR2 ablation resulted in exacerbation of colitis, possibly due to increased apoptosis of colonic epithelial cells[31]. However, in other studies a central role of TNFR2 in mucosal inflammation has been proposed.…”