TY - JOUR
T1 - MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation
AU - Cai, Bishuang
AU - Thorp, Edward B.
AU - Doran, Amanda C.
AU - Subramanian, Manikandan
AU - Sansbury, Brian E.
AU - Lin, Chyuan Sheng
AU - Spite, Matthew
AU - Fredman, Gabrielle
AU - Tabas, Ira
N1 - Funding Information:
We thank Drs. Galina Gusarova and Li Li from the Jahar Bhattacharya laboratory (Columbia University) for helping with the lung histology analysis; and Anita Antes and Dr. Ray Birge (Rutgers University) for providing the Gas6-producing cell line. This work was supported in part by an American Heart Association Post-Doctoral Fellowship grant (to B.C.); National Institutes of Health (NIH) Pathway to Independence K99/R00 Grant HL119587 (to G.F.); and NIH/NHLBI R01 Grants HL107497 and HL075662 (to I.T.) and HL106173 (to M.S.). The fluorescence microscopy experiments used the confocal and specialized microscopy core at Columbia University's Irving Cancer Research Center, and flow analyses used the Columbia Center for Translational Immunology/Diabetes and Endocrinology Research Center Flow Core facility, funded in part by NIH/NIDDK Center Grant 5P30DK063608 and by the Office of the NIH Director under Shared Instrumentation Grant S10OD020056.
PY - 2016/6/7
Y1 - 2016/6/7
N2 - 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 theMer 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 (MertkCR). MertkCR 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.
AB - 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 theMer 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 (MertkCR). MertkCR 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.
KW - 5-lipoxygenase
KW - Efferocytosis
KW - Inflammation resolution
KW - Macrophages
KW - MerTK
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U2 - 10.1073/pnas.1524292113
DO - 10.1073/pnas.1524292113
M3 - Article
C2 - 27199481
AN - SCOPUS:84973397896
SN - 0027-8424
VL - 113
SP - 6526
EP - 6531
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -