Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor andBorrelia burgdorferiOuter Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-Like Receptor 2 Signaling

Abstract

Toll-like receptor 2 (TLR2) and TLR4 play important roles in innate immune responses to various microbial agents. We have previously shown that human dermal endothelial cells (HMEC) express TLR4, but very little TLR2, and respond to LPS, but not to Mycobacterium tuberculosis 19-kDa lipoprotein, unless transfected with TLR2. Here we report that HMEC are unresponsive to several additional biologically relevant TLR2 ligands, including, phenol-soluble modulin (PSM), a complex of three small secreted polypeptides from the skin commensal Staphylococcus epidermidis, soluble tuberculosis factor (STF), and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L). Expression of TLR2 renders HMEC responsive to all these ligands. We further characterized the signaling pathway in response to STF, OspA-L, and PSM in TLR2-transfected HMEC. The TLR2 signaling pathway for NF-κB trans-activation shares the IL-1R signaling molecules. Dominant negative constructs of TLR2 or TLR6 inhibit the responses of STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the concept of functional cooperation between TLR2 and TLR6 for all these TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and overexpression of Tollip inhibits NF-κB activation in response to TLR2 and TLR4 signaling. Collectively, these findings suggest that there is functional interaction between TLR2 and TLR6 in the cellular response to STF and OspA-L in addition to S. epidermidis (PSM) Ags, and that engagement of TLR2 triggers a signaling cascade, which shares the IL-1R signaling molecules, similar to the TLR4-LPS signaling cascade. Our data also suggest that Tollip may be an important constituent of both the TLR2 and TLR4 signaling pathways.

Transcriptional and inflammasome‐mediated pathways for the induction of IL‐1β production by Mycobacterium tuberculosis

“…TLR2 is a receptor for bacterial lipopeptides, which are recognized by TLR2/TLR1 or TLR2/TLR6 heterodimers [30,31]. Cooperation of TLR2 and TLR6 has been described to be involved in recognition of mycobacterial components [32]. In line with this, IL-1b production induced by M. tuberculosis was dependent on TLR2 and TLR6, but not TLR1 (Fig.…”

Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines

“…Pathogens such as M. tuberculosis may elicit release of CXCR3-signaling chemokines from tissue macrophages and immature dendritic cells at the site of infection after recognition by TLR4 [37][38][39]. In addition, mycobacterial signaling via TLR2/TLR6 elicits chemokines that attract PMN [40][41][42][43]. PMN, in turn, guarantee both amplified attraction of T cells and focusing of the reaction to the site of infection via their secretion of CXCR3-signaling chemokines.…”

Toll-like receptors and their role in experimental models of microbial infection

“…18 Other recently identified adaptor proteins that interact with mammalian TLRs include TIR containing adaptor protein (TIRAP) 19 that functions downstream of TLR4 in a MyD88-independent signaling pathway and Toll interacting protein (TOLLIP) 20 that interacts with TLR2, TLR4, and IL-1R and has been shown to downregulate both IL-1b 20 and TLR-mediated signaling in vitro. 21,22 Genetic mapping and regulation of mammalian TLR expression…”

“…Nevertheless, extensive in vitro data implicating TLR2 in the recognition of mycobacterial lipoarabinomannan, 31 a soluble tuberculosis factor, 22 whole Mycobacterium avium, 71 and Mycobacterium tuberculosis 72,73 strongly suggest that one or more TLRs participate in mycobacterial host defense. Published genetic analyses of experimental mycobacterial infection among different strains of inbred mice have identified significant QTL for tuberculosis susceptibility (sst1) on mouse chromosome 1 74 as well as resistance (Trl1-3) on mouse chromosomes 1, 3, and 7.…”