Resolution Potential of Necrotic Cell Death Pathways

Abstract

During tissue damage caused by infection or sterile inflammation, not only damage-associated molecular patterns (DAMPs), but also resolution-associated molecular patterns (RAMPs) can be activated. These dying cell-associated factors stimulate immune cells localized in the tissue environment and induce the production of inflammatory mediators or specialized proresolving mediators (SPMs). Within the current prospect of science, apoptotic cell death is considered the main initiator of resolution. However, more RAMPs are likely to be released during necrotic cell death than during apoptosis, similar to what has been observed for DAMPs. The inflammatory potential of many regulated forms of necrotic cell death modalities, such as pyroptosis, necroptosis, ferroptosis, netosis, and parthanatos, have been widely studied in necroinflammation, but their possible role in resolution is less considered. In this review, we aim to summarize the relationship between necrotic cell death and resolution, as well as present the current available data regarding the involvement of certain forms of regulated necrotic cell death in necroresolution.

Damage-mediated macrophage polarization in sterile inflammation

“…The effects of additional DAMPs such as IL-33, Annexin A1 (ANXA1), and certain inflammatory mediators (PGE2) depend on the cells and/or receptors that sense them. Thus, alterations in the tissue environment can change their effect into an anti-inflammatory effect [reviewed in ( 1 )].…”

“…SPM secretion, resolving D1/E1, lipoxin A4 and maresin1 from dying cells has been demonstrated, and efferocytes engulfing dead cells can also produce SPMs ( 9 ). The common effect of the different SPMs is the enforcement of the M2 differentiation ( 1 ). PS appearing on the surface of dead cells also increases the polarization in the M2 direction through the activation of MerTK receptors on the efferocytes ( 67 ).…”

“…As MerTK and SPM expression increases in M2 cells, a complex positive feedback loop appears between MerTK, SPMs, and M2 cells in the presence of dead cell corps. An increase in the amount of dying cells or M2 cells therefore turns the inflammatory signals in the direction of resolution ( 1 ).…”

“…Diseases associated with inflammation are major contributors to global mortality. Conditions such as cardiovascular and neurodegenerative diseases, cancer, various lung, kidney, and liver diseases, as well as autoimmune diseases, are all connected to sterile inflammation ( 1 , 2 ). The social impact of these diseases and sterile inflammation surpasses that of infectious diseases.…”

“…Pathological sterile inflammation can arise from abnormal modes or intensities of cell death ( 9 , 16 ), the dysregulated release of damage-associated molecular patterns (DAMPs) (as discussed in our review articles ( 1 , 9 )), or failure in transitioning from inflammation to resolution ( 17 ). In this review, we aim to provide a summary of how RAMPs and DAMPs - released during sterile tissue damage - influence the differentiation of monocytes into macrophages.…”