Figure 2.

Necrotic cell death regulates the balance between pro-inflammatory- and pro-resolution-signals inducing necro-inflammation or necro-resolution.Intracellular molecules and molecular patterns associated with damage and resolution (DAMPs and RAMPs) are released from necrotic cells. Various cell types and their inflammatory or anti-inflammatory subpopulations sense these secreted mediators, together with dead cell corps in the tissue environment. Here, pro-inflammatory or pro-resolution mediators, such as SPMs, become dominant, which is determined by the type of cell death and the cells that sense it. Phosphatidylserine (PS) exposed on the surface of dying cells is recognized by MerTK receptors, stimulating the phosphorylation of 5-LOX in efferocytes and, consequently, increasing SPM production. “Don’t eat me” receptors (CD24, CD31, CD47) expressed by dying cells stimulate inhibitory receptors on efferocytes (such as Siglec 10), shifting the balance toward the anti-inflammatory response. The effects of the released factors could be modified by post-translational modifications or by the molecular partners interacting with them. After oxidation, HMGB1 loses its inflammatory potential, while its association with C1q, CD52, or CD24 results in its binding to inhibitory receptors (Siglec 10 or Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1)), converting the effect of these complexes into anti-inflammatory. Extracellular ATP, which promotes inflammation, is degraded into immunosuppressive adenosine by cell surface receptors (CD39 and CD73). The pro-inflammatory or pro-resolution effect of IL-33, ANXA1, and PGE2 depends on the type of cells and/or receptors that perceive them.