Toll-like receptor (TLR) 2 plays a critical role in host defenses against mycobacterial infections. The Arg753Gln (R753Q) TLR2 polymorphism has been associated with increased incidence of tuberculosis and infections with non-tuberculous mycobacteria in human populations, but the mechanisms by which this polymorphism affects TLR2 signaling are unclear. In this study, we determined the impact of the R753Q TLR2 polymorphism on macrophage sensing of Mycobacterium smegmatis. Upon infection with M. smegmatis, macrophages from knock-in (KI) mice harboring R753Q TLR2 expressed lower levels of TNF-α, IL-1β, IL-6 and IL-10 compared to cells from wild-type (WT) mice but both R753Q TLR2 and WT mice exhibited comparable bacterial burdens. The decreased cytokine responses in R753Q TLR2-expressing macrophages were accompanied by impaired phosphorylation of IL-1R associated kinase (IRAK)-1, p38 and ERK1/2 MAPKs and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), suggesting that the R753Q TLR2 polymorphism alters functions of the myeloid differentiation primary response protein (MyD88)-IRAK-dependent signaling axis. Supporting this notion, HEK 293 cells stably transfected with YFP-tagged R753Q TLR2 displayed reduced recruitment of MyD88 to TLR2, decreased NF-κB activation, and impaired IL-8 expression upon exposure to M. smegmatis. Collectively, our results indicate that the R753Q polymorphism alters TLR2 signaling competence, leading to impaired MyD88-TLR2 assembly, reduced phosphorylation of IRAK-1, diminished activation of MAPKs and NF-κB, and deficient induction of cytokines in macrophages infected with M. smegmatis.
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