title: 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 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.
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; Department of Physiology, Columbia University, New York, NY 10032;
authors.forename: Bishuang
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611;
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; Department of Physiology, Columbia University, New York, NY 10032;
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Doran
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; Department of Physiology, Columbia University, New York, NY 10032;
authors.forename: Manikandan
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Brian E
authors.initials: BE
authors.lastname: Sansbury
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; Department of Physiology, Columbia University, New York, NY 10032;
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Matthew
authors.initials: M
authors.lastname: Spite
authors.affiliation: Center for Cardiovascular Sciences, Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208 fredmag@mail.amc.edu iat1@columbia.edu.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fredman
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; Department of Physiology, Columbia University, New York, NY 10032; fredmag@mail.amc.edu iat1@columbia.edu.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase
chemical_list: D018836:Inflammation Mediators; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D001094:Arachidonate 5-Lipoxygenase; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: 5-lipoxygenase; MerTK; efferocytosis; inflammation resolution; macrophages