The inflammatory response to cell death

Abstract

When cells die in vivo, they trigger an inflammatory response. The ensuing hyperemia, leak of plasma proteins, and recruitment of leukocytes serve a number of useful functions in host defense and tissue repair. However, this response can also cause tissue damage and contribute to the pathogenesis of a number of diseases. Given the key role of inflammation in these processes, it is important to understand the underlying mechanisms that drive this response. Injured cells release danger signals that alert the host to cell death. Some of these molecules are recognized by cellular receptors that stimulate the generation of proinflammatory mediators. Other molecules released by dead cells stimulate the generation of mediators from extracellular sources. The resulting mediators then orchestrate the inflammatory response, eliciting its various vascular and cellular components. Dead cells also release danger signals that activate dendritic cells and promote the generation of immune responses to antigens. Here we review what is presently known about the sterile inflammatory response and its underlying mechanisms.

Figure 1

Acute inflammation induced by cell death. (A) Normal myocardium showing the expected absence of leukocytes. (B) Infarcted myocardium showing neutrophils surrounding dead cardiac myocytes. 40X magnification.

Figure 2

Responses to different forms of cell death. Cells undergoing necrosis lose membrane integrity and leak their intracellular components some of which serve as danger signals that stimulate inflammation. Apoptotic cells may not stimulate inflammation if they are ingested by phagocytes before they release their intracellular contents. Moreover, during this process apoptotic cells can stimulate phagocytes to produce anti-inflammatory cytokines. However, if the apoptotic cells are not cleared rapidly they release danger signals when they proceed into secondary necrosis.

Figure 3

Examples of cellular receptors that sense infection and cell death. TLR detect infections by recognizing microbial molecules that are structurally different from mammalian ones (distinguishing self from nonself). In addition, there is emerging evidence that they can recognize certain autologous molecules that are normally hidden intracellularly (“hidden self”) but are released when cells die. Once stimulated TLR lead to the activation of the transcription factor NFkB and sometimes IRF3 which then turn on many of the key components of the inflammatory response. The danger signal MSU stimulates a pathway that contains the intracellular Nod-like receptor NALP3 and results in the production of the proinflammatory cytokine IL-1.

Figure 4

Proinflammatory molecules released from dying cells. Cells contain a number of different danger signals that can potentially stimulate inflammation through different mechanisms. Some of these signal are intracellular molecules that trigger inflammation by directly stimulating cells to make proinflammatory cytokines. Others work by generating proinflammatory mediators from extracellular components such as the extracellular matrix and complement.