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

Research output: Contribution to journalArticle

70 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 (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.

Original languageEnglish (US)
Pages (from-to)6526-6531
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number23
DOIs
StatePublished - Jun 7 2016

Keywords

  • 5-lipoxygenase
  • Efferocytosis
  • Inflammation resolution
  • Macrophages
  • MerTK

ASJC Scopus subject areas

  • General

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