How dying cells alert the immune system to danger

Abstract

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

Fig. 1. Stranger and danger models

Dendritic cells (DCs) are present in all tissues where they gather antigens from the local environment but are not in an immunostimulatory state. In Janeway's “stranger” model antigen presenting cells (later appreciated to be DC) were endowed with pattern recognition receptors that recognized the unique features of microbial molecules (pathogen-associated molecular patterns or PAMPs). When PAMPs were present, for example, from an infection or adjuvant, then DCs were stimulated to migrate to lymphoid tissues and present both antigen and costimulatory molecules to T cells. In Matzinger's danger model , the key event controlling the initiation of an immune response was not infection, but the production of danger signals (DAMPs) from cells stressed, damaged and/or dying in the local tissue. These were postulated to act on DCs in ways that also caused them to migrate and present antigens to T cells in an immunostimulatory manner. It has been speculated that DAMPs might be produced in response to PAMPs and actually be the final mediator promoting immune responses in all situations, including infection. This may occur, however it is also possible, and in our view likely, that DAMPs and PAMPs can alert the immune system to a problem independently and possibly even in a synergistic manner.

Fig. 2. Discriminating between viable cells, necrosis and apoptosis

The hidden-self model proposes that innate immune cells have receptors that detect certain intracellular molecules, called damage-associated molecular patterns (DAMPs), that are normally hidden in the interior of cells and which are only revealed after necrosis. This model can explain why live cells, which contain preexisting danger signals, don't stimulate the innate immune system. Moreover, it can also explain why necrotic cells always stimulate the innate immune system, whereas apoptotic cells are only stimulatory in some situations but not others . This is because necrotic cells always lose membrane permeability and release their intracellular contents. By contrast, apoptotic cells initially maintain membrane integrity. If apoptotic cells are then rapidly cleared by phagocytes, then the dead cells don't release their intracellular DAMPs and the immune system is not stimulated. However, if apoptotic cells are not rapidly cleared, as may occur in a solid organ, then they undergo secondary necrosis and become permeable. The resulting release of DAMPs then stimulates the innate immune system. So, the event that communicates “danger” is not how the cell dies per se, but whether or not it eventually loses membrane integrity and releases its intracellular contents into the extracellular millieu. This concept of hidden signals being revealed may also apply to DAMPs of extracellular origin (e.g. when revealed through the action of enzymes released after cell damage) and even, as has been proposed, hidden portions of molecules.

Figure 3. Cell death and inflammation

Necrotic cell death releases intracellular damage-associated molecular patterns (DAMPs) that are recognized by receptors on leukocytes and possibly other host cells, stimulating the generation of proinflammatory cytokines such as interleukin-1 (IL-1). Other molecules that are exposed or released from dead cells act on extracellular components to generate mediators (for example, complement fragments) or DAMPs (for example, fragments of extracellular matrix) that then trigger the production of proinflammatory cytokines from host cells. The proinflammatory mediators act on local vascular endothelium causing them to become `leaky' and attract neutrophils and monocytes. Once in the tissue, these soluble and cellular defences attempt to neutralize or contain microorganisms or other injurious agents if present. They also clear dead cells and stimulate tissue repair.