Signals, receptors, and cytokines involved in the immunomodulatory and anti-inflammatory properties of apoptotic cells

Abstract

Cell death can occur controlled by apoptosis or rather uncontrolled by necrosis. The decision to initiate an inflammatory response has to be made for dying cells, which arise by hundreds of billions each day. They carry valuable information with respect to the possible influence of pathogens. Apoptosis and the swift phagocytosis of dying cells by macrophages and neighboring tissue cells act together to remove supernumerary, dangerous, or damaged cells. Apoptosis, in contrast to necrosis, normally does not induce inflammation or organ damage. Apoptotic cells maintain their membrane integrity for a relatively long time, thereby preventing the release of tissue damaging contents and proinflammatory mediators. In addition, early recognition and efficient, non-inflammatory removal of the apoptotic cells essentially contribute to preventing an inflammatory response and organ damage. Furthermore, apoptotic cells can even actively suppress inflammation and modulate immune responses by inhibiting the release of proinflammatory cytokines but augmenting the secretion of anti-inflammatory and immunomodulatory cytokines from monocytes/macrophages (MoMa) and dendritic cells. The anti-inflammatory effect of apoptotic cells is mediated by the thrombospondin receptor (CD36) on MoMa and, most likely, other surface receptors, which are not yet molecularly identified. Elevation of intracellular cAMP levels seems to be critically involved in the induction of the anti-inflammatory state in MoMa. These findings have important implications for clinical medicine. On the one hand side, exposure to high amounts of apoptotic cells in conditions such as cancer or certain viral infections may result in clinically relevant immunosuppression. On the other hand side, therapeutic induction of apoptosis can ameliorate inflammatory diseases. Furthermore, pathogens can misuse apoptotic cells as ‘Trojan horses’ to silently infect and paralyze macrophages. We point out that several pathogens such as HIV, Plasmodium falciparum, Trypanosoma cruzi and Leishmania major mimic apoptotic cells for silent entry and immune escape. Albeit apoptotic cells exert immunosuppressive effects, the impaired clearance of dead cells causes the release of potential autoantigens and, thereby, fosters autoimmunity. At least in a subgroup of patients with systemic lupus erythematosus impaired phagocytosis of dead cells by macrophages has been observed and may contribute to the etiopathogenesis of this autoimmune disorder.