Pseudomonas aeruginosa infection augments inflammation through miR-301b repression of c-Myb-mediated immune activation and infiltration

microRNAs (miRNAs) play critical roles in various biological processes including cell proliferation, development, and host defense. However, the molecular mechanism for miRNAs in regulating bacterial-induced inflammation remains largely unclear. Here we report that miR-301b augments pro-inflammatory response during pulmonary infection and caffeine (CAF) suppresses miR-301b’s effect and thereby augmenting respiratory immunity. LPS treatment or Pseudomonas aeruginosa infection induces miR-301b expression via a TLR4/MyD88/NF-κB pathway. Importantly, CAF decreases miR-301b expression through negative regulation of the cAMP/PKA/NF-κB axis. Further, c-Myb is identified as a target of miR-301b, which positively modulates anti-inflammatory cytokines IL-4 and TGF-β1, but negatively regulates pro-inflammatory cytokines MIP-1α and IL-17A. Moreover, repression of miR-301b results in increased transcription of c-Myb and elevated levels of neutrophil infiltration, thereby alleviating infectiou symptoms in mice. These findings reveal miR-301b as a new controller of inflammatory response by repressing c-Myb function to inhibit anti-inflammatory response to bacterial infection, representing a novel mechanism for balancing inflammation.