62 : The integrated stress response regulates the severity of DSS colitis via chop-mediated control of inflammatory cytokine gene expression

Abstract

The integrated stress response (ISR) engages cellular mechanisms that enable eukaryotic cells to respond to diverse stresses. Multiple studies have shown that the ISR can impact on immune and inflammatory responses by regulating the magnitude and duration of pro-inflammatory cytokine expression via the induction of the transcription factor cEBP homologous protein (CHOP). Indeed, in bone marrow derived macrophages cell stress elevates IL-6 gene expression via CHOP-dependent prolongation of transcription. To determine the impact of this mechanism in vivo we employed dextran sodium sulfate (DSS)-induced colitis in irradiated mice reconstituted with bone marrow from either wt or CHOP-/- mice. While disease initiation appears to be comparable in both wt and CHOP-/- chimeras, recovery is markedly improved in mice with CHOP-/- bone marrow. This is reflected by reduced clinical scores (weight loss, diarrhea, rectal bleeding), reduced myeloid cell infiltration and inflammatory histopathology, and increased survival. Moreover, IL-6 levels in colon tissue and in CD11b+ cells from the lamina propria were significantly lower in mice with CHOP-/- bone marrow. The ISR can also impact on T cell responses through arginase or indolamine deoxygenase mediated depletion of essential amino acids (arg, trp) and activation of the eIF2a-specific protein kinase GCN2. Irradiated mice reconstituted with GCN2-/- bone marrow exhibit DSS-induced colitis that is comparable to or more severe than that seen in mice receiving wt bone marrow. Because GCN2 deficiency does not appear to compromise IL-6 expression in myeloid cells from DSS-treated mice, the protective effect of CHOP deficiency appears to be operating in the myeloid cell population and not in the T cell population.