MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

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 cellsurface 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.MerTK | efferocytosis | inflammation resolution | macrophages | 5-lipoxygenase

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

“…Upon activation, AXL/MERTK not only facilitate the action of efferocytosis but also trigger antiinflammatory responses in macrophages by inhibiting Toll-like receptor (TLR) signaling and increasing the expression of suppressor of cytokine 1 (SOCS1) and SOCS3 (21,22). Under inflammatory conditions, AXL and MERTK can be cleaved from the cell membrane, decreasing availability of the cell surface receptors for activation (23,24). These soluble forms of the receptors can be detected in the blood and tissue, and may compete with membrane-form receptors for the binding of protein S and GAS6.…”

“…peritonitis, ischemia/reperfusion lung injury, and atherosclerosis (24). Both AXL and MERTK were highly expressed on macrophages, but only AXL transcription was rapidly upregulated between days 1 and 3 after ICH.…”

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis

“…Although this may seem counterintuitive, there is a precedent for this pattern of UPR activation, both in our work and ticular, can trigger the production of proresolving mediators by macrophages (17,41,50,51). Indeed, increasing lesional MerTK by preventing its degradation not only suppresses plaque progression, but also increases resolution mediators in atherosclerotic lesions (39). The possible role of excessive macrophage CaMKII activation in the impaired resolution response in atherosclerosis will be an important topic for future investigation.…”

“…Mertk -/-mice have been described previously (39). Camk2g fl/fl mice were generated as previously described (39 Quantitative PCR.…”

“…Mertk -/-mice have been described previously (39). Camk2g fl/fl mice were generated as previously described (39 Quantitative PCR. RNA was isolated from macrophages using an RNeasy Kit (QIAGEN), and cDNA was synthesized from RNA (ranging from 500 ng to 1 μg per reaction) using a cDNA synthesis kit (Applied Biosystems, catalog 4374966).…”