Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Abstract

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

“…As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32]. In view of the CD14 and LPS independence of the epithelial response to P fimbriated E. coli, we speculated that TLR4 signalling might utilise adaptor proteins other than MyD88 and TIRAP.…”

“…In myeloid cells, the LPS/LPS-binding protein complex binds CD14 and MD-2 [4,5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

“…Tlr4 -/- [45], Tlr2 -/- [46], Myd88 -/- [30] and Tirap -/- [29] mice were generated in the C57BL/6 mouse background, and Trif -/- [47] and Tram -/-[48] mice were generated in the C57BL/6/129 mouse background and were made in the BIKEN animal facilities (Osaka, Japan). Lps2, a non-functional codominant allele of Trif, was induced by N-ethyl-N-nitrosourea mutagenesis on a pure C57BL/6 mouse background [49] in the Scripps Institute animal facilities (La Jolla CA).…”

“…1). The results showed that P fimbriated E. coli trigger a TLR4-dependent response in vivo in the urinary tract and that the urinary tract mucosa remains inert when exposed to a non-adhesive strain, or when TLR4 is inactivated.Involvement of Trif Lps2/Lps2 /Tram in the response to P fimbriated E. coliIn myeloid cells, the LPS/LPS-binding protein complex binds 5] and the subsequent dimerisation of TLR4 recruits IL-1R-associated serine kinase-4 (IRAK-4) via the adaptors myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP) [29,30]. As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32].…”

NF-κB and the immune response

“…TLR4 signaling is relatively unique amongst TLRs in that the effector adaptors are one step removed from the receptor. For example, MyD88 recruitment to the receptor complex depends upon the TIR-domain containing adapter protein (TIRAP, also known as Mal) (Fitzgerald et al, 2001;Horng et al, 2002;Yamamoto et al, 2002). TLR2 also requires TIRAP to bridge MyD88 to the receptor; however it is believed that other MyD88-utilizing TLRs directly recruit MyD88.…”