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Immunol."],"abstract":"<jats:p>I\u03baB proteins regulate the inhibition and activation of NF-\u03baB transcription factor complexes. While classical I\u03baB proteins keep NF-\u03baB complexes inactive in the cytoplasm, atypical I\u03baB proteins act on activated NF-\u03baB complexes located in the nucleus. Most of the knowledge regarding the function of I\u03baB proteins has been collected<jats:italic>in vitro<\/jats:italic>, while far less is known regarding their impact on activation and regulation of immune responses during<jats:italic>in vivo<\/jats:italic>infections. Combining<jats:italic>in vivo Listeria monocytogenes<\/jats:italic>(Lm) infection with comparative<jats:italic>ex vivo<\/jats:italic>transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, I\u03baB<jats:sub>NS<\/jats:sub>-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced I\u03baB<jats:sub>NS<\/jats:sub>-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high<jats:italic>Nfkbid<\/jats:italic>promoter activity uncovered in Ly6C<jats:sup>high<\/jats:sup>inflammatory monocytes prompted us to further characterize the specific contribution of I\u03baB<jats:sub>NS<\/jats:sub>in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C<jats:sup>high<\/jats:sup>monocytes primed during Lm infection in the absence of I\u03baB<jats:sub>NS<\/jats:sub>displayed a blunted response compared to wild type-derived Ly6C<jats:sup>high<\/jats:sup>monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as<jats:italic>Il6<\/jats:italic>,<jats:italic>Nos2<\/jats:italic>and<jats:italic>Il1\u03b2<\/jats:italic>. Strikingly, altered monocyte activation in I\u03baB<jats:sub>NS<\/jats:sub>-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking I\u03baB<jats:sub>NS<\/jats:sub>exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and I\u03baB<jats:sub>NS<\/jats:sub><jats:sup>-\/-<\/jats:sup>mice for most of the analyzed mediators, IL-10 was virtually undetectable in I\u03baB<jats:sub>NS<\/jats:sub>-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for I\u03baB<jats:sub>NS<\/jats:sub>during Lm infection with I\u03baB<jats:sub>NS<\/jats:sub>-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C<jats:sup>high<\/jats:sup>monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified I\u03baB<jats:sub>NS<\/jats:sub>as molecular driver of inflammation in listeriosis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1028789","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T05:02:52Z","timestamp":1671685372000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["I\u03baBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune 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