MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Bishuang Cai; Edward B. Thorp; Amanda C. Doran; Manikandan Subramanian; Brian E. Sansbury; Chyuan Sheng Lin; Matthew Spite; Gabrielle Fredman; Ira Tabas

doi:10.1073/pnas.1524292113

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Bishuang Cai, Edward B. Thorp, Amanda C. Doran, Manikandan Subramanian, Brian E. Sansbury, Chyuan Sheng Lin, Matthew Spite, Gabrielle Fredman^*, Ira Tabas

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

187 Scopus citations

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 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 (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.

Original language	English (US)
Pages (from-to)	6526-6531
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	23
DOIs	https://doi.org/10.1073/pnas.1524292113
State	Published - Jun 7 2016

Funding

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.

Keywords

5-lipoxygenase
Efferocytosis
Inflammation resolution
Macrophages
MerTK

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1524292113

Cite this

@article{3ef7aba1bf6841d3a467a2279865d3d7,

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 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.",

keywords = "5-lipoxygenase, Efferocytosis, Inflammation resolution, Macrophages, MerTK",

author = "Bishuang Cai and Thorp, {Edward B.} and Doran, {Amanda C.} and Manikandan Subramanian and Sansbury, {Brian E.} and Lin, {Chyuan Sheng} and Matthew Spite and Gabrielle Fredman and Ira Tabas",

note = "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.",

year = "2016",

month = jun,

day = "7",

doi = "10.1073/pnas.1524292113",

language = "English (US)",

volume = "113",

pages = "6526--6531",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "23",

}

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

UR - http://www.scopus.com/inward/record.url?scp=84973397896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973397896&partnerID=8YFLogxK

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 -

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this