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.

炎症消退可以平衡过度炎症并恢复损伤后的组织稳态。解决失败会导致许多慢性炎症性疾病的病理。解析是由内源性专门的促解析介质 (SPM) 介导的，这些介质是通过脂氧合酶 (LOX) 从长链脂肪酸衍生而来的。 5-LOX 在两类 SPM 的生物合成中发挥着关键作用：脂氧素和分解素。非磷酸化形式的 5-LOX 的细胞质定位对于 SPM 生物合成至关重要，而磷酸化 5-LOX 的核定位则促进促炎性白三烯的产生。我们之前表明，MerTK（巨噬细胞上的胞吞作用受体）通过增加非磷酸化细胞质 5-LOX 的丰度来促进 SPM 生物合成。我们现在表明，人巨噬细胞中 MerTK 的激活导致 ERK 介导的编码肌浆/内质网钙 ATP 酶 2 (SERCA2) 的基因表达，从而降低胞质 Ca ²⁺浓度并抑制钙/钙调蛋白依赖性蛋白的活性激酶 II (CaMKII)。这反过来又降低了丝裂原激活蛋白激酶 (MAPK) p38 和激酶 MK2 的活性，导致非磷酸化细胞质形式 5-LOX 的丰度增加，并增强了 SPM 生物合成。在酵母聚糖诱导的腹膜炎模型中，巨噬细胞 MerTK 激活促进消退，抑制 ERK 激活则延迟消退，其特征是组织渗出物中中性粒细胞数量增加和 SPM 数量减少。 这些发现有助于我们了解 MerTK 信号传导如何诱导 5-LOX 衍生的 SPM 生物合成，并提出了一种治疗策略，以在消退缺陷促进疾病进展的情况下促进炎症消退。