An Essential Role of the NF-κB<i>/</i>Toll-Like Receptor Pathway in Induction of Inflammatory and Tissue-Repair Gene Expression by Necrotic Cells

TLDR

Tissue damage from infection or injury can cause necrosis, which triggers inflammation, whereas apoptosis does not, and the mechanisms underlying this difference remain unclear. We found that necrotic, but not apoptotic, cells activate NF‑κB through TLR2, inducing inflammatory and tissue‑repair genes such as KC and MIP‑2 in fibroblasts and macrophages, revealing a novel endogenous activation of the NF‑κB/TLR2 pathway.

Abstract

Abstract Tissue damage induced by infection or injury can result in necrosis, a mode of cell death characterized by induction of an inflammatory response. In contrast, cells dying by apoptosis do not induce inflammation. However, the reasons for underlying differences between these two modes of cell death in inducing inflammation are not known. Here we show that necrotic cells, but not apoptotic cells, activate NF-κB and induce expression of genes involved in inflammatory and tissue-repair responses, including neutrophil-specific chemokine genes KC and macrophage-inflammatory protein-2, in viable fibroblasts and macrophages. Intriguingly, NF-κB activation by necrotic cells was dependent on Toll-like receptor 2, a signaling pathway that induces inflammation in response to microbial agents. These results have identified a novel mechanism by which cell necrosis, but not apoptosis, can induce expression of genes involved in inflammation and tissue-repair responses. Furthermore, these results also demonstrate that the NF-κB/Toll-like receptor 2 pathway can be activated both by exogenous microbial agents and endogenous inflammatory stimuli.