TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events

Abstract

Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor α quickly returned to baseline in tlr3−/− mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3−/− mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

“…34 In another study, using a model of bacterial peritonitis induced by cecal ligation and puncture, RNA from necrotic cells could amplify the inflammatory response in a TLR-3-dependent manner. 35 However, in our study, recruitment of neutrophils was independent of TLR-3, and in contrast to the Cavassani study, it required the functions of TLR-2 and TLR-9. The discrepancies between our results and the work of Chen et al 33 and Cavassani et al 35 could be explained by differences in the form of cell death (apoptosis versus primary necrosis) and death stimuli (doxorubicin versus heat shock or ischemia in combination with bacterial peritonitis).…”

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…TLR3 has been implicated in various pathological conditions including viral infection, sepsis and retinal degeneration. 8,25,41 Although previous studies have mainly focused on a direct pro-inflammatory pathway in TLR3 signaling, our data suggest that the RIP3-dependent necrotic pathway is also important in amplifying tissue inflammation and degeneration in these diseases.…”

“…7 Damage-associated molecular patterns (DAMPs) released from necrotic cells enhance the inflammatory response and tissue injury. 8,9 Although necrosis was thought to be an uncontrolled process of cell death, it is now known to proceed through regulated components in certain instances. 10 Receptor-interacting protein 3 (RIP3) is a key mediator of programmed necrosis induced through death receptors or toll-like receptors (TLRs).…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…In vivo, TLR3 is required for injury-induced acute inflammatory responses. During experimental polymicrobial septic peritonitis and ischemic gut injury, the levels of inflammatory cytokines quickly drop to baseline in TLR3-defi cient mice [18] . Thus, dying cells (both apoptotic and necrotic) are sources that provide self nucleic acids to activate endosomal TLRs.…”