The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

Abstract

Toll-like receptor 2 (TLR2) plays a critical role in host defenses against mycobacterial infections. The 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 Upon infection with, macrophages from knock-in mice harboring R753Q TLR2 expressed lower levels of TNF-α, IL-1β, IL-6, and IL-10 compared with cells from WT mice, but both R753Q TLR2- and WT-derived macrophages exhibited comparable bacterial burdens. The decreased cytokine responses in R753Q TLR2-expressing macrophages were accompanied by impaired phosphorylation of IL-1R-associated kinase 1 (IRAK-1), p38, ERK1/2 MAPKs, and p65 NF-κB, suggesting that the R753Q TLR2 polymorphism alters the functions of the myeloid differentiation primary response protein 88 (MyD88)-IRAK-dependent signaling axis. Supporting this notion, HEK293 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 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.

Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation

“…Furthermore, the TLR2 polymorphism R753Q is associated with a severe phenotype and higher levels of IgE in AD patients . Others showed an altered function of MyD88 signaling in mice macrophages bearing the TLR2 polymorphism R753Q . It has been reported that the frequency of R753Q is higher in AD children, while others showed a similar distribution in healthy children and concluded that the association between AD and R753Q is lacking .…”

IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis

“…For infections, wild‐type (WT) or IRAK4 KI mice were i.p. administered M. smegmatis (5 × 10 6 CFUs) or L. monocytogenes (2 × 10 4 CFU), similar to doses used in previous reports . Six hours post infection (hpi), blood samples were obtained by retroorbital punctures and serum was prepared to analyze cytokines.…”

“…Six hours post infection (hpi), blood samples were obtained by retroorbital punctures and serum was prepared to analyze cytokines. At 48 hpi, spleens and livers were homogenized in PBS containing protease and phosphatase inhibitors (ThermoFisher Scientific, Waltham, MA) and bacterial CFUs were enumerated by plating organ homogenates on the respective agars . To generate bone marrow‐derived macrophages (BMDMs), bone marrow cells from femurs and tibias were differentiated for 7 days in DMEM (Mediatech, Herndon, VA), supplemented with 10% FBS (Atlanta Biologicals, Flowery Branch, GA), 2 mM l ‐glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin (complete RPMI) and 15% L929 cell‐conditioned, macrophage‐colony‐stimulating factor‐containing supernatant …”

“…administered M. smegmatis (5 × 10 6 CFUs) or L. monocytogenes (2 × 10 4 CFU), similar to doses used in previous reports. 16,17 Six hours post infection (hpi), blood samples were obtained by retroorbital punctures and serum was prepared to analyze cytokines. At 48 hpi, spleens and livers were homogenized in PBS containing protease and phosphatase inhibitors (ThermoFisher Scientific, Waltham, MA) and bacterial CFUs were enumerated by plating organ homogenates on the respective agars.…”

Evaluation of TLR-2 sera levels in a sample of Iraqi pulmonary TB patients

“…TLR 2 is taken part in immunity against infection of MTB. The capability of toll like receptor 2 to contribute in the white blood cells triggering by MTB and different responses mediation activated by these cells propose that protein of TLR may work discrete functions in the mycobacteria immune responses [10]. A study showed that TLR 2 existence is unessential for increasing sufficient inherited resistance to aerobic infection with M. tuberculosis [11].…”