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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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MKP-1−/− macrophage population subsets display a mixed pro- and antiinflammatory phenotype at early stages of the muscle repair process and premature cytokine silencing at later stages caused by p38 hyperactivation. (A) Genes were analyzed by RT-PCR in isolated macrophage populations at 1, 3, and 6 d postinjury (P.I.). (bottom) A model of the temporal macrophage phenotypes in WT and MKP1−/− damaged muscles during repair. (B) F4/80-positive cells present in injured muscles of WT and MKP1−/− mice systemically treated with SB203580 (from 1 to 3 or 3 to 6 d) were analyzed for Ly-6C expression by flow cytometry. Total number of cells per milligram of injured muscle tissue was calculated. Means ± SEM of at least three experiments. ***, P < 0.001; **, P < 0.01.
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fig3: MKP-1−/− macrophage population subsets display a mixed pro- and antiinflammatory phenotype at early stages of the muscle repair process and premature cytokine silencing at later stages caused by p38 hyperactivation. (A) Genes were analyzed by RT-PCR in isolated macrophage populations at 1, 3, and 6 d postinjury (P.I.). (bottom) A model of the temporal macrophage phenotypes in WT and MKP1−/− damaged muscles during repair. (B) F4/80-positive cells present in injured muscles of WT and MKP1−/− mice systemically treated with SB203580 (from 1 to 3 or 3 to 6 d) were analyzed for Ly-6C expression by flow cytometry. Total number of cells per milligram of injured muscle tissue was calculated. Means ± SEM of at least three experiments. ***, P < 0.001; **, P < 0.01.

Mentions: We investigated whether the MKP-1–p38 pathway would be mechanistically implicated in the early transition of pro- to antiinflammatory macrophages. Unlike WT macrophages, FACS-isolated MKP-1−/− muscle macrophages (Fig. S3, C and D) of both Ly-6Chigh and Ly-6Clow populations expressed high levels of antiinflammatory cytokines in addition to proinflammatory cytokines 3 d after injury (Fig. 3 A and Fig. S4 A). Because in WT macrophages, antiinflammatory cytokine expression was restricted to the Ly-6Clow population in 6-d damaged muscle after injury (Fig. 3 A, right), our results indicate that loss of MKP-1 anticipates the antiinflammatory gene program after tissue damage, resulting in a temporal overlap of pro- and antiinflammatory cytokine expression. Interestingly, p38 inhibition in vivo by SB203580 treatment of MKP-1−/− damaged tissue restored both cell number and cytokine expression pattern of MKP-1−/− Ly-6Chigh and Ly-6Clow macrophages at 3 d after injury, resembling those of WT macrophages (Fig. 3, A and B). It is worth mentioning that the ex vivo analysis of FACS-sorted macrophages within injured muscle has allowed us to specifically study the effect of p38 inhibition on macrophage cytokine production, hence bypassing potential effects of SB203580 on other cell types. Consistent with the in vivo results, in response to an inflammatory stimulus (either lipopolysaccharide [LPS] or recombinant HMGB1), cultured MKP-1−/− macrophages simultaneously expressed high levels of pro- and antiinflammatory cytokines, coinciding with p38 hyperactivation in comparison with WT macrophages (Fig. S4 B and not depicted; Chi et al., 2006; Hammer et al., 2006; Wu et al., 2006; Zhao et al., 2006). Thus, during the early stages of tissue repair, MKP-1 controls both the overall magnitude of the inflammatory response as well as the timing of macrophage polarization via p38 down-regulation.


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)

MKP-1−/− macrophage population subsets display a mixed pro- and antiinflammatory phenotype at early stages of the muscle repair process and premature cytokine silencing at later stages caused by p38 hyperactivation. (A) Genes were analyzed by RT-PCR in isolated macrophage populations at 1, 3, and 6 d postinjury (P.I.). (bottom) A model of the temporal macrophage phenotypes in WT and MKP1−/− damaged muscles during repair. (B) F4/80-positive cells present in injured muscles of WT and MKP1−/− mice systemically treated with SB203580 (from 1 to 3 or 3 to 6 d) were analyzed for Ly-6C expression by flow cytometry. Total number of cells per milligram of injured muscle tissue was calculated. Means ± SEM of at least three experiments. ***, P < 0.001; **, P < 0.01.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig3: MKP-1−/− macrophage population subsets display a mixed pro- and antiinflammatory phenotype at early stages of the muscle repair process and premature cytokine silencing at later stages caused by p38 hyperactivation. (A) Genes were analyzed by RT-PCR in isolated macrophage populations at 1, 3, and 6 d postinjury (P.I.). (bottom) A model of the temporal macrophage phenotypes in WT and MKP1−/− damaged muscles during repair. (B) F4/80-positive cells present in injured muscles of WT and MKP1−/− mice systemically treated with SB203580 (from 1 to 3 or 3 to 6 d) were analyzed for Ly-6C expression by flow cytometry. Total number of cells per milligram of injured muscle tissue was calculated. Means ± SEM of at least three experiments. ***, P < 0.001; **, P < 0.01.
Mentions: We investigated whether the MKP-1–p38 pathway would be mechanistically implicated in the early transition of pro- to antiinflammatory macrophages. Unlike WT macrophages, FACS-isolated MKP-1−/− muscle macrophages (Fig. S3, C and D) of both Ly-6Chigh and Ly-6Clow populations expressed high levels of antiinflammatory cytokines in addition to proinflammatory cytokines 3 d after injury (Fig. 3 A and Fig. S4 A). Because in WT macrophages, antiinflammatory cytokine expression was restricted to the Ly-6Clow population in 6-d damaged muscle after injury (Fig. 3 A, right), our results indicate that loss of MKP-1 anticipates the antiinflammatory gene program after tissue damage, resulting in a temporal overlap of pro- and antiinflammatory cytokine expression. Interestingly, p38 inhibition in vivo by SB203580 treatment of MKP-1−/− damaged tissue restored both cell number and cytokine expression pattern of MKP-1−/− Ly-6Chigh and Ly-6Clow macrophages at 3 d after injury, resembling those of WT macrophages (Fig. 3, A and B). It is worth mentioning that the ex vivo analysis of FACS-sorted macrophages within injured muscle has allowed us to specifically study the effect of p38 inhibition on macrophage cytokine production, hence bypassing potential effects of SB203580 on other cell types. Consistent with the in vivo results, in response to an inflammatory stimulus (either lipopolysaccharide [LPS] or recombinant HMGB1), cultured MKP-1−/− macrophages simultaneously expressed high levels of pro- and antiinflammatory cytokines, coinciding with p38 hyperactivation in comparison with WT macrophages (Fig. S4 B and not depicted; Chi et al., 2006; Hammer et al., 2006; Wu et al., 2006; Zhao et al., 2006). Thus, during the early stages of tissue repair, MKP-1 controls both the overall magnitude of the inflammatory response as well as the timing of macrophage polarization via p38 down-regulation.

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