Transcription repressor Hes1 is a selective regulator of TLR-induced CXCL1 expression and neutrophil responses (IRM5P.708)

Abstract

Abstract Chemokine-mediated neutrophil recruitment to sites of inflammation is a critical initial step in host defense and inflammatory responses. However, neutrophil recruitment must be tightly regulated to avoid inappropriate immune activation which may lead to autoimmune and inflammatory diseases. Here we show that transcription repressor hairy and enhancer of split 1 (Hes1) suppresses TLR-induced expression of CXCL1, a chemokine crucial for recruiting neutrophils. Interestingly, Hes1 deficiency does not affect expression of other pro-inflammatory cytokines such as Tnf and Il1b. Hes1 negatively regulates Cxcl1 expression and neutrophil recruitment in vivo in LPS-induced peritonitis. In addition, deficiency of Hes1 exacerbated severity of K/BxN serum-induced arthritis in which neutrophils play a key pathogenic role. Mechanistically, regulation of Cxcl1 expression by Hes1 is at the transcriptional level but not via modification of TLR-induced canonical signaling events. Instead, Hes1 represses Cxcl1 productive transcription by attenuating occupancy of a positive-transcription elongation complex P-TEFb at the Cxcl1 gene locus and thus preventing subsequent recruitment of serine 2-phosphorylated RNA polymerase II. In summary, our results identify Hes1 as a novel homeostatic regulator of CXCL1 expression and neutrophil responses and suggest that targeting Hes1-mediated repressive pathway may represent a new therapeutic approach to selectively curbing neutrophil-mediated inflammation.