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p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair


Details
Publication Date: 
17/10/2011
Authors: 
Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P.
Citation: 
J Cell Biol. 2011 Oct 17;195(2):307-22. Epub 2011 Oct 10.
DOI: 
10.1083/jcb.201104053
Abstract
Repair of damaged tissue requires the coordinated action of inflammatory and
      tissue-specific cells to restore homeostasis, but the underlying regulatory
      mechanisms are poorly understood. In this paper, we report new roles for MKP-1
      (mitogen-activated protein kinase [MAPK] phosphatase-1) in controlling macrophage
      phenotypic transitions necessary for appropriate muscle stem cell-dependent
      tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to
      antiinflammatory macrophage transition and the later progression into a
      macrophage exhaustion-like state characterized by cytokine silencing, thereby
      permitting resolution of inflammation as tissue fully recovers. p38
      hyperactivation in macrophages lacking MKP-1 induced the expression of
      microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin
      homologue) levels, thereby extending AKT activation. In the absence of MKP-1,
      p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene
      program and final cytokine silencing in macrophages, resulting in impaired tissue
      healing. Such defects were reversed by temporally controlled p38 inhibition.
      Conversely, miR-21-AKT interference altered homeostasis during tissue repair.
      This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, 
      miR-21, and AKT activities may have implications in chronic inflammatory
      degenerative diseases.