Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway

TLDR

TRIF/TICAM‑1 complexes with RIP3 after TLR3/TLR4 activation, driving RIP3‑dependent necrosis in macrophages. RIP3‑dependent, TNF‑α‑independent necrosis is induced by TLR3/4 activation through TRIF, and mice lacking RIP3 or TRIF are protected from macrophage loss, cytokine elevation, and ROS‑mediated necrosis, showing that multiple upstream pathways converge on RIP3 during innate immune responses.

Abstract

We report here that mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent but TNF-α-independent necrosis when Toll-like receptors (TLR) 3 and 4 are activated by poly(I:C) and LPS, respectively. An adaptor protein, Toll/IL-1 receptor domain-containing adapter inducing IFN-β (TRIF/TICAM-1), which is dispensable for TNF-α-induced necrosis, forms a complex with RIP3 upon TLR3/TLR4 activation and is essential for TLR3/TLR4-induced necrosis. Mice without RIP3 or functional TRIF did not show macrophage loss and elevation of inflammatory cytokines when they were exposed to LPS. Necrosis in mouse macrophages induced by either TNFR or TLR3/TLR4 is executed by reactive oxygen species. Taken together, these data indicate that there are multiple upstream necrosis-initiating signaling pathways converging on the RIP3 during an innate immune response to viral and bacterial infections in mammals.