The Toll-like receptor (TLR) family consists of ten germline-encoded microbe sensors that are crucial for host defence. The theory is that each receptor triggers an innate immune response that is appropriate for the class of pathogen that the receptor recognizes. But, differences between TLR signal-transduction pathways that might result in such tailored responses have been hard to find. Now, two studies published in Nature show that the adaptor molecule TIRAP (also known as MAL) has a restricted role in a shared TLR2 and TLR4 signal-transduction pathway.
TIRAP is structurally similar to the adaptor protein MYD88, which links the TLRs and interleukin-1 receptors (IL-1Rs) to downstream signalling pathways. MYD88 is essential for the induction of cytokine secretion by all TLR ligands, but the lipopolysaccharide (LPS) receptor TLR4 can stimulate the upregulation of expression of co-stimulatory receptors on dendritic cells (DCs) in the absence of MYD88. Initial in vitro studies indicated that TIRAP might function in this MYD88-independent pathway. But, the Tirap-knockout mice described by Yamamoto et al. and Horng et al. show that this is not the case.
Horng and co-workers found that in response to triggering of TLR2 or TLR4, Tirap−/− B cells had impaired proliferative responses and Tirap−/− DCs produced markedly reduced levels of pro-inflammatory cytokines. But, responses to a TLR9 ligand (CpG DNA) were normal in these cells, and injection of the TLR5 ligand flagellin into Tirap−/− mice induced the expression of normal levels of cytokines. Yamamoto et al. showed that the production of pro-inflammatory cytokines in response to LPS and various ligands for TLR2 is impaired markedly in Tirap−/− macrophages. Furthermore, Tirap−/− mice were completely resistant to LPS-induced shock. But, the responses of Tirap−/− macrophages to synthetic ligands for TLR7 and TLR3, and CpG DNA, were intact.
In contrast to Myd88−/− mice, both groups showed that IL-1 signalling is not compromised in Tirap−/− mice. So, together, these papers show that TIRAP is dispensable for TLR3, TLR5, TLR7, TLR9 and IL-1R function, but has a specific role in TLR2 and TLR4 signal-transduction pathways.
Similar to MYD88, TIRAP has a crucial role in the activation of nuclear factor-κB and mitogen-activated protein kinases by TLR2 and TLR4. And Tirap−/− mice and Myd88−/− mice have similarly defective responses to LPS, which indicates that TIRAP might be involved in a MYD88-dependent pathway. To test this, Yamamoto and co-workers generated Myd88−/−Tirap−/− mice. The LPS-induced upregulation of expression of co-stimulatory molecules on DCs (a MYD88-independent event) occurred normally in these double-knockout mice, so TIRAP is clearly not part of the MYD88-independent pathway.
ORIGINAL RESEARCH PAPERS
Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324–329 (2002)
Horng, T. et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002)
Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001)