Abstract
IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκB(NS)-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκB(NS)-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6C(high) inflammatory monocytes prompted us to further characterize the specific contribution of IκB(NS) in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C(high) monocytes primed during Lm infection in the absence of IκB(NS) displayed a blunted response compared to wild type-derived Ly6C(high) monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκB(NS)-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 IκB(NS) 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 IκB(NS) (-/-) mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκB(NS)-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκB(NS) during Lm infection with IκB(NS)-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C(high) monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκB(NS) as molecular driver of inflammation in listeriosis.