C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation

Abstract

Loss of intestinal epithelial cell (IEC) homeostasis and apoptosis negatively affect intestinal barrier function. Uncontrolled activation of the unfolded protein response (UPR) in IEC contributes to an impaired barrier and is implicated in the pathogenesis of inflammatory bowel diseases. However, the contribution of the UPR target gene C/EBP homologous protein (CHOP), an apoptosis-associated transcription factor, to inflammation-related disease susceptibility remains unclear. Consistent with observations in patients with ulcerative colitis, we show that despite UPR activation in the epithelium, CHOP expression was reduced in mouse models of T-cell-mediated and bacteria-driven colitis. To elucidate the molecular mechanisms of IEC-specific CHOP expression, we generated a conditional transgenic mouse model (Chop(IEC Tg/Tg)). Chop overexpression increased the susceptibility toward dextran sodium sulfate (DSS)-induced intestinal inflammation and mucosal tissue injury. Furthermore, a delayed recovery from DSS-induced colitis and impaired closure of mechanically induced mucosal wounds was observed. Interestingly, these findings seemed to be independent of CHOP-mediated apoptosis. In vitro and in vivo cell cycle analyses rather indicated a role for CHOP in epithelial cell proliferation. In conclusion, these data show that IEC-specific overexpression impairs epithelial cell proliferation and mucosal tissue regeneration, suggesting an important role for CHOP beyond mediating apoptosis.

Use of animal models in elucidating disease pathogenesis in IBD

“…Treatment with an anti-TL1A antibody decreases the amount of IFNγ and IL-17A produced and attenuates weight loss, colon shortening, and the histologic inflammation seen in this model of chronic colitis. These findings are corroborated in two other models of T cell-mediated chronic colitis [92, 93]. TL1A’s effect on the production of Th1- and Th17-related cytokines is supported using T cells and macrophages isolated from the intestinal LP and peripheral blood (PB) of patients with CD.…”

Mitochondrial function controls intestinal epithelial stemness and proliferation

“…We expected the UPR-related transcription factor CHOP to be involved, since CHOP has been shown to induce cell cycle arrest43. Recently, we generated epithelial-specific Chop transgenic mice and demonstrated that high levels of CHOP attenuate cell cycle progression leading to delayed epithelial proliferation and wound closure in response to colonic injuries34. Nevertheless, using Chop −/− Hsp60 Δ/ΔIEC mice in this study did not indicate any impact of CHOP-mediated signals on mitochondrial dysfunction-associated loss of proliferation and stemness.…”

“…MT-UPR in mammals is rather poorly described, but mechanistic studies in a primate-derived cell line identified the transcription factor CHOP and its cofactor C/EBPβ to induce expression of MT-UPR responsive chaperones like HSP60, its co-chaperone HSP10 and proteases like ATP-dependent caseinolytic peptidase proteolytic subunit homologue (CLPP)313233. By using an epithelial-specific Chop transgenic mouse model, we recently showed delayed epithelial proliferation and intestinal wound healing in response to increased levels of CHOP, suggesting CHOP to affect intestinal homeostasis by attenuating cell cycle progression34.…”

C/EBP homologous protein (CHOP) gene deficiency attenuates renal ischemia/reperfusion injury in mice

“…Recent studies 314 have demonstrated that CHOP is associated with the inflammatory re-315 sponse [37,38]; activation of caspase 11-caspase 1 by CHOP stimulates 316 IL-1 and IL-1β productions in the lung exposed to LPS. In this present 317 study we found that that I/R induced inflammatory response, and the 318 increase of inflammatory response was attenuated by CHOP deficiency, 6.…”