Research ArticleInflammation

MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

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Sci. Signal.  25 Sep 2018:
Vol. 11, Issue 549, eaar3721
DOI: 10.1126/scisignal.aar3721

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Promoting resolution

The active and coordinated process of inflammation resolution is critical for tissue homeostasis, and defective resolution is associated with chronic inflammatory diseases. Specialized proresolving mediators (SPMs) are fatty acid derivatives that counteract the effects of proinflammatory factors, triggering resolution and tissue repair. SPM biosynthesis depends on the cytosolic localization of the nonphosphorylated form of the lipoxygenase 5-LOX, whereas the nuclear translocation of phosphorylated 5-LOX results in inflammatory leukotriene production. Cai et al. showed that signaling by the efferocytosis receptor MerTK in macrophages activated an ERK-dependent pathway that inhibited the phosphorylation of 5-LOX, thus promoting SPM production. Inhibition of ERK activation in a mouse model of peritonitis delayed resolution, suggesting that the MerTK-ERK pathway might be therapeutically manipulated to promote inflammation resolution.

Abstract

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca2+ concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX–derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

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