Abstract
The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic:nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cell-surface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk(CR)). Mertk(CR) mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.
Highlights
The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases
Mer proto-oncogene tyrosine kinase (MerTK) is a macrophage cell-surface protein that mediates a key process in inflammation resolution, efferocytosis, by interacting with Gas6 or protein S, which are bridging molecules that bind externalized phosphatidylserine on apoptotic cells (ACs) [13, 14]
Plasma solMer is increased in patients with active systemic lupus erythematosus and rheumatoid arthritis [23, 24], and cell-surface MerTK is lower in macrophages in ADAM metallopeptidase domain 17 (ADAM17)-rich areas in advanced human atherosclerotic lesions [25]
Summary
Mertk−/− cohort, there were no significant differences or LTB4 or combined prostaglandins (Fig. S2 C and D). By using the parameters described above, the resolution interval was improved approximately twofold in the MertkCR mice (∼13 vs 24 h) This improvement was associated with a marked decrease in exudate sol-Mer and an increase in cell-surface MerTK on exudate macrophages (Fig. 3B). To determine whether the increase in SPMs was linked to the improvement in resolution in MertkCR mice, we prevented SPM action by intraperitoneal injection of a blocking antibody against the common RvD1/LXA4 receptor ALX/FPR2 This treatment prevented the proresolving benefit of MertkCR, as indicated by a twofold elevation in PMNs at 30 h (Fig. 3G). The cytoplasmic:nuclear 5-LOX ratio in exudate macrophages 30 h after intraperitoneal zymosan was decreased in Mertk−/− and increased in MertkCR mice vs WT mice (Fig. 5D). These combined data support a model in which MerTK activation increases the ratio of cytoplasmic-to-nuclear 5-LOX and decreases p-S271–5-LOX, which leads to increased production of SPMs
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