Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-?B activation.

ABSTRACT: Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-?B signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-?B activation occurs through a blockade in transforming growth factor ?-activated kinase 1 (TAK1) and IKK? activation. As a consequence, NF-?B (p65) phosphorylation is reduced, its translocation to the nucleus is inhibited and NF-?B-mediated inflammatory cytokine transcription is suppressed. Gene Set Enrichment Analysis reveals that this suppression of NF-?B activation is not restricted to post-translational modifications of the canonical NF-?B pathway, but is also imprinted at the transcriptional level. Thus neutrophils exert a sustained anti-inflammatory phenotypic reprogramming of the macrophage, which is reflected by the sustained reduction in the release of pro- but not anti- inflammatory cytokines from the macrophage. Together, our findings identify a novel apoptosis-independent mechanism by which neutrophils regulate the mediator profile and reprogramming of monocytes/macrophages, representing an important nodal point for inflammatory control.

SUBMITTER: Marwick JA 

PROVIDER: S-EPMC5986789 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature