Abstract

Production of pro-inflammatory cytokines and chemokines is tightly controlled by multiple signaling pathways to ensure adequate immune responses yet avoiding excessive inflammation. Here, we show that expression of several cytokines and chemokines essential for immune and inflammatory responses is regulated by the Notch signaling pathway that is commonly associated with developmental processes but not with regulation of inflammation. In macrophages, signaling by Notch receptor via RBP-J, the main nuclear transducer of Notch signaling, augmented toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages such as IL-12 and thus of innate immune responses to Listeria monocytogenes . We found that Notch–RBP-J signaling controlled expression of the transcription factor IRF8 that induced downstream M1 macrophage–associated genes. RBP-J promoted the synthesis of IRF8 protein by selectively augmenting kinase IRAK2–dependent signaling via TLR4 to the kinase MNK1 and downstream translation-initiation control through eIF4E. Our results define a signaling network in which signaling via Notch–RBP-J and TLRs is integrated at the level of synthesis of IRF8 protein and identify a mechanism by which heterologous signaling pathways can selectively regulate TLR-induced expression of cytokines such as IL-12. Besides controlling expression of cytokines, the Notch pathway also regulates production of certain chemokine molecules. A canonical Notch target gene Hes1 encodes a transcription repressor that selectively suppressed expression of a key neutrophil chemoattractant CXCL1. As a result, Hes1 deficiency in mice led to enhanced neutrophil recruitment to sites of inflammation and exacerbated disease in a neutrophil-dependent model of inflammatory arthritis, supporting an essential role for Hes1 in negatively regulating neutrophil responses in vivo . Collectively, our results identify the Notch pathway as a critical regulator of cytokine and chemokine-mediated inflammation and suggest that therapeutics targeting Notch signaling hold promise to selectively modulate inflammatory responses under human autoimmune and inflammatory conditions.

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