NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection (116.15)

Abstract

Abstract Tolerance to bacterial cell-wall components including gram-positive bacterial lipoprotein (BLP) represents an essential regulatory mechanism during bacterial infection. Our previous work has demonstrated that BLP-induced tolerance, characterised by hyporesponsiveness in producing proinflammatory cytokines and simultaneously enhanced antimicrobial functions, protects against microbial sepsis-related lethality. However, the underlying mechanisms remain unidentified. In this study we reported that upon S. aureus or E. coli challenge, significantly enhanced IκBα phosphorylation and p65 translocation into the nucleus were observed in BLP-tolerised bone marrow-derived macrophages (BMM), indicating that NF-κB is activated in BLP-tolerised macrophages during bacteria infection. To further clarify whether activation of the NF-κB pathway is required for efficient bacterial killing by BLP-tolerised macrophages, we used two NF-κB inhibitors, SN50 and SC-154. Both inhibitors substantially restrained BLP-tolerised macrophage-induced intracellular bacterial killing, and this was closely associated with delayed phagolysosome fusion. Furthermore, the expression of LAMP-1 and Rab5, two membrane-trafficking regulators participated the process of phagosome maturation was significantly downregulated when the NF-κB pathway was blocked. Collectively, our results highlight a novel role of the NF-κB pathway in bactericidal activity displayed by BLP-tolerised macrophages during microbial infection.