“The reason why this study has been highly cited is because this is the first evidence showing the involvement of a TIR domain-containing adaptor molecule other than MyD88 in fractionating the MyD88-dependent pathway as well as the existence of additional adaptor molecule(s) involved in the MyD88-independent pathway.”

The discovery of Toll-Like Receptor (TLR) family members has provided a new insight into the field of immunology. TLRs have been shown to recognize microbial components such as LPS and peptidoglycan and induce cellular immune responses. Activation of signaling cascades via TLRs originates from the intracellular region called the Toll/IL-1 Receptor (TIR) domain where a cytoplasmic TIR domain-containing adaptor molecule, MyD88, binds and signals downstream to the nucleus and activates inflammatory cytokine production. Although MyD88-deficient mice completely abolished proinflammatory cytokine production in response to all TLR ligand stimuli, they still remained responsive via TLR3 and TLR4 that induced type I interferon production. Thus, signaling cascades via TLRs are separated into two groups: the MyD88-dependent pathway for all TLRs and the MyD88-independent pathway for TLR3 and TLR4. The molecular mechanisms for the MyD88-independent pathway have been extensively studied by a number of groups and finally led to identification of the second TIR domain-containing adaptor molecule, TIRAP (also known as Mal). Initial in vitro studies indicated that TIRAP is specifically involved in TLR4-mediated signaling, including both the MyD88-dependent and the MyD88-independent pathways. To elucidate the physiological role of TIRAP, we generated TIRAP-deficient mice. The analysis of TIRAP-deficient mice clearly showed that TIRAP deficiency affected the MyD88-dependent pathway via TLR4, but not the MyD88-independent pathway. In addition, TIRAP-deficient mice showed severely impairment in TLR1/TLR2/TLR6 responses, but not in TLR3, TLR5, TLR7 and TLR9. Therefore, we concluded that TIRAP is not responsible for the MyD88-independent pathway, rather a molecule for the MyD88-dependent pathways shared by TLR2(TLR1/TLR6) and TLR4. The reason why this study has been highly cited is because this is the first evidence showing the involvement of a TIR domain-containing adaptor molecule other than MyD88 in fractionating the MyD88-dependent pathway as well as the existence of additional adaptor molecule(s) involved in the MyD88-independent pathway.