Missing in action—The meaning of cell death in tissue damage and inflammation

Abstract

Billions of cells die every day in higher organisms as part of the normal process of tissue homeostasis. During special conditions like in development, acute infections, mechanical injuries, and immunity, cell death is a common denominator and it exerts profound effects in the outcome of these scenarios. To prevent the accumulation of aged, superfluous, infected, damaged and dead cells, professional phagocytes act in a rapid and efficient manner to clear the battle field and avoid spread of the destruction. Neutrophils are the most abundant effector immune cells that extravasate into tissues and can turn injured tissues into gory battle fields. In peace times, neutrophils tend to patrol tissues without provoking inflammatory reactions. We discuss in this review actual and forgotten knowledge about the meaning of cell death during homeostatic processes and drive the attention to the importance of the action of neutrophils during patrolling and for the maintenance or recovery of the homeostatic state once the organism gets attacked or injured, respectively. In this fashion, we disclose several disease conditions that arise as collateral damage of physiological responses to death.

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

“…Solid lines indicate concentration normalized to 10 6 cells; dashed lines, total concentrations; =, value below detection limit; dashed red circles, maxima for concentrations/10 6 cells; solid blue circles, maxima for absolute concentrations. and immunoregulatory functions (24). In cancer, immunoregulatory neutrophils are often referred to as granulocytic myeloid-derived suppressor cells.…”

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface

“…Chronic inflammatory responses to necrotic tissue are prevented by NETs that form barriers between the necrotic areas and the healthy surrounding tissues . Neutrophil‐driven inflammations are often terminated by proteolysis of cytokines and chemokines by NET‐born serine proteases limiting the inflammatory focus . However, chronic and pathologic accumulation of noncleared NETs reportedly contributes to the perpetuation of autoimmune responses and autoinflammatory tissue damage …”

“…8,9 Neutrophildriven inflammations are often terminated by proteolysis of cytokines and chemokines by NET-born serine proteases limiting the inflammatory focus. [10][11][12] However, chronic and pathologic accumulation of noncleared NETs reportedly contributes to the perpetuation of autoimmune responses and autoinflammatory tissue damage. [13][14][15][16] The presence of neutrophils and NETs in ocular inflammatory diseases like dry eye 17 and allergy 18 has been reported.…”

Death, danger & immunity: Fundamental mechanisms linking pathogenic or iatrogenic cell death events to immune responses

“…This system is designed to avoid excessive inflammatory reactions that could cause local dysfunctions including scar formation and tissue fibrosis, as well as systemic disease. Moreover, physiological cell death usually does not cause any detrimental autoimmune response, meaning that immune tolerance usually is maintained upon exposure to dead‐cell antigens …”

“…Moreover, physiological cell death usually does not cause any detrimental autoimmune response, meaning that immune tolerance usually is maintained upon exposure to dead-cell antigens. 2 It is only when cell death occurs at a massive scale and when it is induced by non-physiological stimuli such as infectious pathogens, chemical agents, or irradiation that it results in inflammatory or immune reactions that have an impact on whole-body physiology. 3,4 The present issue of Immunological Review is dealing with the mechanistic links between Death, Danger and Immunity.…”