19MODE OF ACTION

Efferocytosis: removal of exhausted, mainly apoptotic neutrophils to prevent tissue damage; many are removed by macrophages

Macrophage phenotype switch: reprogramming triggered by efferocytosis, from a proinflammatory to a proresolution phenotype, contributing towards postresolution immune tolerance and prevention of autoimmunity

Neutrophil phenotype switch: reprogramming to an anti-inflammatory type, promoting neutrophil reverse migration

Treatments that suppress inflammation may also suppress its resolution In severe conditions, an anti-inflammatory strategy is mandatory to prevent tissue destruction or an overwhelming inflammatory process. Alternatively, a proresolution strategy could be considered the treatment of choice.[Fullerton 2016]

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibiting the cyclooxygenase-2 (COX-2) pathway are a mainstay of inflammation treatment. COX-2 promotes biosynthesis of many proinflammatory mediators, but some are equally important for initiation of inflammation resolution (Figure 2). [Sugimoto 2016]

For example, prostaglandin E2 (PGE2), one of the major products of COX-2, which is usually inhibited by NSAIDs, is involved in: A lipid mediator class switch[Sugimoto 2016]

A macrophage phenotype switch[Sugimoto 2016]

A neutrophil phenotype switch[Loynes 2018]

Figure 2 Transition to resolution is linked to a switch in cellular phenotypes and chemical mediators.

LTs

COX, cyclooxygenase; LOX, lipoxygenase; LTs, leukotrienes; PGs, prostaglandins; PGE2, prostaglandin E2; SPMs, specialized proresolving mediators.