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

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.

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

“…The finding that necrotic material alone or combined with normal IgG was inactive is somewhat surprising because necrotic cells are considered to be proinflammatory. They can, for instance, induce maturation and activation of dendritic cells (45,46), and cause production of proinflammatory cytokines such as chemokines and tumor necrosis factor ␣ in macrophages (47,48).…”

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

“…In general, loss of membrane integrity results in an efflux of cytosolic factors into the surrounding medium, which is an acute danger signal capable of initiating inflammation (6,7). As previously shown in fibroblasts and macrophages, unlike apoptotic cells in which the cell membranes stay intact for a prolonged period of time, necrotic cells which totally lose their membrane integrity, induce genes involved in inflammation and tissue repair (8). Different endogenous molecules, such as heat-shock proteins (hsp), 3 high mobility group box 1, and uric acid, have been identified to alert the immune system (9 -11).…”

“…Toll-like receptors are expressed on different cell types and their importance has been investigated extensively on professional APCs, such as macrophages and dendritic cells. In addition to exogenous factors such as bacteria, viruses, and parasites, recent studies have also revealed a role of the Toll/ IL-1 receptor family in regulating responses to endogenous factors (8,(13)(14)(15). Hepatocytes express multiple TLR family members and are therefore thought to be able to respond to various pathogens, but whether they are also responsive to endogenous factors is largely unknown (16).…”

Mechanisms of immune resolution

“…One could speculate that the presence of a significant component of immune cell apoptosis in the septic (129) or traumatized animal as we and others have reported on MØs from septic or traumatized subjects might serve as a stimulant for the increased release of anti-inflammatory mediators. Conversely, necrotic cell debris from damaged tissues has been shown in vitro to be a proinflammatory stimuli (13,130,131). However, as tissue injury of various origins induces both apoptotic and necrotic cell death, it is unlikely that in vivo effects will be so simplistic (130,(132)(133)(134)(135)(136)(137).…”

“…Many of these agents, such as microbial wall components, lipopolysaccharide, muramyl dipeptide, lipoteichoic acid, activate immune cells directly via pattern recognition receptors (Toll-like receptors) (10,11). Similarly, endogenous cellular proteins, such as heat shock proteins, various oligonucleotide forms produced by necrotic cell damage, or phospholipids/glycolipids, released in the wound by damaged tissue can interact with these Toll-like receptors (12)(13)(14). Interestingly, although not thought of as agents involved in pathogen pattern recognition, a number of the components of the complement cascade and coagulation pathway that are activated by the process of injury or infection can also serve as such immune cell activating signals (15,16).…”