IκBNS-deficiency protects mice from fatal Listeria monocytogenes infection by blunting pro-inflammatory signature in Ly6Chigh monocytes and preventing exaggerated innate immune responses

I kappa B proteins regulate the inhibition and activation of NF-kappa B transcription factor complexes. While classical I kappa B proteins keep NF-kappa B complexes inactive in the cytoplasm, atypical I kappa B proteins act on activated NF-kappa B complexes located in the nucleus. Most of the knowledge regarding the function of I kappa B 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, I kappa B-NS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced I kappa B-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 I kappa B-NS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C(high) monocytes primed during Lm infection in the absence of I kappa B-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 Il1 beta. Strikingly, altered monocyte activation in I kappa B-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 I kappa B-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 I kappa B-NS (-/-) mice for most of the analyzed mediators, IL-10 was virtually undetectable in I kappa B-NS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for I kappa B-NS during Lm infection with I kappa B-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 I kappa B-NS as molecular driver of inflammation in listeriosis.

Automated summary

I kappa B proteins play a crucial role in regulating the activation and inhibition of NF-kappa B transcription factor complexes. In this study, it was found that the absence of I kappa B-NS resulted in a transcriptional repression of immune responses, particularly in myeloid cells. Further investigation revealed that the blunted inflammatory response of monocytes in I kappa B-NS-deficient mice contributed to their resistance against Lm infection and reduced immunopathology.