Regulation of 4-1BBL-mediated inflammation at the late phase of TLR response (P1228)

Toll-like receptor (TLR)-mediated signaling leads to the expression of inflammatory genes, and this process is sustained for the duration of inflammatory response. The TNF superfamily member 4-1BB ligand (4-1BBL) plays an essential role in sustained TNF production in macrophages. 4-1BBL expression was induced by the initial TLR signaling, and 4-1BBL formed a complex with TLRs at a late phase to trigger the secondary signaling. TLR/4-1BBL-mediated late phase signaling was dependent on TIRAP and IRAK2, and the downstream TRAF6/TAK1/TAB1 complex formed and induced MAPK activation. During the early phase of TLR4 response, the TLR4, MyD88, TIRAP, and IRAK2 formed an initial complex, and then the secondary TLR4/4-1BBL/TIRAP/IRAK2 complex formation was followed to initiate the late phase signaling that sustains TNF production in macrophages. Inhibition of the late phase TIRAP activity downregulated sustained TNF production in macrophages and further ameliorated LPS-induced septic shock. Thus, the late phase TLR/4-1BBL/TIRAP/IRAK2 signaling is critical for sustained inflammation in innate immune cells.