In former times (cellular) waste was clearly defined by distinguishing the non- or anti-inflammatory apo cell death form the primary nec one. Only the latter was thought to lead to immune activation and inflammation. Nowadays, waste is renamed resource and it becomes more and more evident that various forms of cell death exist, each comprising a distinct inflammatory potential, additionally modulated by the microenvironment. Regarding signalling pathways, late apo cells behave under certain conditions identically to early apo ones. However, late apo cells which have lost their membrane integrity and have, therefore, become secondarily nec release intracellular contents like alarmins leading to immune activation and inflammation. Live can be so easy and death is so complicated: even very early apo cells can lead to immune activation by exposing proteins on their cellular surface, e.g. the ER protein calreticulin, which lead to their phagocytosis by DC and consecutively to an activation of the adaptive immune system.
HMGB1 is the most prominent example of a group of molecules called alarmins or danger signals. It has the potential to activate cells of the innate immune system (MΦ) and those of the adaptive (DC) one. Also HMGB2 has chemoattractant activity for inflammatory cells. In conditions of clearance abnormalities as observed in SLE, non-ingested apo cells may undergo secondary nec with a concomitant release of danger signals. Further modifications of those molecules like oxidation also influence their immunological properties. Waste-derived molecules have, therefore, an outstanding impact on auto-immune and inflammatory responses.
Furthermore, the waste itself can influence adhesive properties of immune cells. Additionally, the dying and dead cells display characteristic surface changes like the appearance of membrane glycoconjugates and the release of ACdMV and apo blebs. These and many other apo and nec cell-dependent abnormalities could predispose to the development of chronic autoimmunity. Apo and nec cells may act as guard to alert close-by viable cells to local environmental changes. The exposure to more intense or prolonged stimuli leads to various forms of “guarding waste” which can be differently phagocytosed by pro- or anti-inflammatory MΦ or can directly stimulate plasmacytoid dendritic cells to secrete inflammatory cytokines.
The micromilieu is of importance for the inflammatory potential of waste-derived molecules as shown for UA. A plethora of experiments presented in the articles of this issue affirm that immune responses are appropriately adapted to the waste, to the damage that has occurred!