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

Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P - J. Cell Biol. (2011)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.

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.

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Proposed model for the role of the p38–MKP-1 balance in controlling ordered macrophage transitions during tissue repair.
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fig8: Proposed model for the role of the p38–MKP-1 balance in controlling ordered macrophage transitions during tissue repair.

Mentions: Interestingly, it has been described that upon endoplasmic reticulum stress or proapoptotic signals, p38 promotes survival of skin macrophages through direct activation of AKT by MK2 (Seimon et al., 2009). Moreover, the PI3K–AKT pathway negatively regulates MAPKs and proinflammatory gene expression in BM-stimulated macrophages in vitro (Luyendyk et al., 2008). We now propose that p38, by inducing IL-1β at the early proinflammatory macrophage stage after injury, stimulates TGFβ expression in antiinflammatory macrophages. Indeed, p38 inhibition at early stages after injury reduces IL-1β expression in proinflammatory cells and affects TGFβ expression in antiinflammatory muscle macrophages (unpublished data). Macrophage-produced TGFβ, in turn, will further promote miR-21 maturation and subsequent PTEN down-regulation and AKT activation, thereby affecting cytokine gene silencing and macrophage cell number as tissue repair advances. Additionally, we demonstrated that p38 activation could directly induce miR-21 gene transcription in macrophages (Fig. 6 H), likely through AP-1 binding sites on the miR-21 promoter (Qi et al., 2009; Roy et al., 2009; Ribas and Lupold, 2010), reinforcing the idea that p38 might promote miR-21 expression in macrophages by direct and indirect mechanisms. Together, our results allow us to draw a model in which p38–MKP-1 and AKT–PTEN pathways act sequentially and interact with each other through cross-regulatory feedback mechanisms at different levels (Fig. 8).


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

Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P - J. Cell Biol. (2011)

Proposed model for the role of the p38–MKP-1 balance in controlling ordered macrophage transitions during tissue repair.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3198158&req=5

fig8: Proposed model for the role of the p38–MKP-1 balance in controlling ordered macrophage transitions during tissue repair.
Mentions: Interestingly, it has been described that upon endoplasmic reticulum stress or proapoptotic signals, p38 promotes survival of skin macrophages through direct activation of AKT by MK2 (Seimon et al., 2009). Moreover, the PI3K–AKT pathway negatively regulates MAPKs and proinflammatory gene expression in BM-stimulated macrophages in vitro (Luyendyk et al., 2008). We now propose that p38, by inducing IL-1β at the early proinflammatory macrophage stage after injury, stimulates TGFβ expression in antiinflammatory macrophages. Indeed, p38 inhibition at early stages after injury reduces IL-1β expression in proinflammatory cells and affects TGFβ expression in antiinflammatory muscle macrophages (unpublished data). Macrophage-produced TGFβ, in turn, will further promote miR-21 maturation and subsequent PTEN down-regulation and AKT activation, thereby affecting cytokine gene silencing and macrophage cell number as tissue repair advances. Additionally, we demonstrated that p38 activation could directly induce miR-21 gene transcription in macrophages (Fig. 6 H), likely through AP-1 binding sites on the miR-21 promoter (Qi et al., 2009; Roy et al., 2009; Ribas and Lupold, 2010), reinforcing the idea that p38 might promote miR-21 expression in macrophages by direct and indirect mechanisms. Together, our results allow us to draw a model in which p38–MKP-1 and AKT–PTEN pathways act sequentially and interact with each other through cross-regulatory feedback mechanisms at different levels (Fig. 8).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.

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.

Show MeSH
Related in: MedlinePlus