Macrophages in smoking environment exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow nicotine to "educate" macrophages are incompletely understood. Here, we identified that nicotine transiently activates and subsequently deactivates monocytes, leading to reduced anti-infective capability of macrophages. This deactivation results in a suppression of IL-17-producing cell expansion through decreased IL-1β production. Mechanistically, nicotine induces the expression of IRAK-M in macrophages, which inhibits NF-κB signaling and restrains NLRP3 inflammasome-mediated IL-1β production. Moreover, the induction of IRAK-M by nicotine is mediated through α7 nAChR binding, which activates downstream STAT3 and AKT signaling pathways. Targeting the interaction between nicotine and α7 nAChR can decrease IRAK-M expression and restore LPS-mediated NLRP3 inflammasome-driven IL-1β production. Collectively, these findings elucidate how nicotine modulates macrophage function through complex signaling mechanisms, ultimately impacting their anti-infective responses and inflammatory processes.
Keywords: IL-1β; IRAK-M; Immunosuppressive macrophages; NF-κB; Nicotine; Th17 cells.
© 2024. The Author(s).