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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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A dysregulated inflammation underlies the defective muscle regeneration of MKP1−/− mice. (A) Effect of bone marrow (BM) transplantation. (left) Number of infiltrating macrophages after BM transplantation at 10 d after injury. (right) CSA of regenerating myofibers in gastrocnemius muscles after BM transplantation. (B) Frequency curves of myofiber size distribution in regenerating gastrocnemius muscles after BM transplantation. BM donors are enclosed in parentheses. Means ± SEM of at least three experiments. ***, P < 0.001.
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fig2: A dysregulated inflammation underlies the defective muscle regeneration of MKP1−/− mice. (A) Effect of bone marrow (BM) transplantation. (left) Number of infiltrating macrophages after BM transplantation at 10 d after injury. (right) CSA of regenerating myofibers in gastrocnemius muscles after BM transplantation. (B) Frequency curves of myofiber size distribution in regenerating gastrocnemius muscles after BM transplantation. BM donors are enclosed in parentheses. Means ± SEM of at least three experiments. ***, P < 0.001.

Mentions: To clarify the relative contribution of inflammatory cell– versus satellite cell–intrinsic MKP-1 functions during muscle tissue repair, we undertook distinct experimental approaches. First, we evaluated whether transplantation of MKP-1–expressing bone marrow (BM) cells could restore muscle regeneration capacity in MKP-1−/− mice after injury. Transplantation of WT BM not only restored normal inflammation, but more importantly, it completely rescued the defective muscle regeneration in MKP-1−/− mice (MKP-1−/−(WT BM)) when compared with WT(MKP-1−/− BM), as indicated by the decreased macrophage number and the increased CSA of regenerating fibers at 10 d after injury, respectively. This data demonstrates that BM/inflammatory cell MKP-1 expression is critical for muscle repair (Fig. 2, A and B). Second, to ascertain the intrinsic contribution of MKP-1 to satellite cell functions, we analyzed the satellite cell progeny of WT and MKP-1−/− single myofibers ex vivo. We found no difference in the number of myofiber-associated satellite cells expressing Pax7 at basal stage or 48 h and Myogenin at 72 h in both genotypes (Fig. S2 D). Furthermore, no differences were observed in the proliferation, differentiation, migration, and fusion rates of cultured WT and MKP-1−/− satellite cells, correlating with a similar p38 activation pattern during the differentiation process (Fig. S2, E–I). Remarkably, addition of conditioned media (CM) from in vitro–activated primary MKP-1−/− macrophages to cultured satellite cells increased their proliferation rate compared with CM from WT macrophages (Fig. S3 A). In contrast, CM from MKP-1−/− macrophages, but not WT CM, reduced the extent of satellite cell differentiation (Fig. S3 B) and fusion (not depicted). Interestingly, these effects were reversed by specific neutralization of the cytokine TNF in MKP-1−/− CM (Fig. S3, A and B), suggesting that the inhibitory actions of MKP-1−/− macrophage-secreted factors on satellite cell functions may be exerted through proinflammatory cytokines.


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)

A dysregulated inflammation underlies the defective muscle regeneration of MKP1−/− mice. (A) Effect of bone marrow (BM) transplantation. (left) Number of infiltrating macrophages after BM transplantation at 10 d after injury. (right) CSA of regenerating myofibers in gastrocnemius muscles after BM transplantation. (B) Frequency curves of myofiber size distribution in regenerating gastrocnemius muscles after BM transplantation. BM donors are enclosed in parentheses. Means ± SEM of at least three experiments. ***, P < 0.001.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: A dysregulated inflammation underlies the defective muscle regeneration of MKP1−/− mice. (A) Effect of bone marrow (BM) transplantation. (left) Number of infiltrating macrophages after BM transplantation at 10 d after injury. (right) CSA of regenerating myofibers in gastrocnemius muscles after BM transplantation. (B) Frequency curves of myofiber size distribution in regenerating gastrocnemius muscles after BM transplantation. BM donors are enclosed in parentheses. Means ± SEM of at least three experiments. ***, P < 0.001.
Mentions: To clarify the relative contribution of inflammatory cell– versus satellite cell–intrinsic MKP-1 functions during muscle tissue repair, we undertook distinct experimental approaches. First, we evaluated whether transplantation of MKP-1–expressing bone marrow (BM) cells could restore muscle regeneration capacity in MKP-1−/− mice after injury. Transplantation of WT BM not only restored normal inflammation, but more importantly, it completely rescued the defective muscle regeneration in MKP-1−/− mice (MKP-1−/−(WT BM)) when compared with WT(MKP-1−/− BM), as indicated by the decreased macrophage number and the increased CSA of regenerating fibers at 10 d after injury, respectively. This data demonstrates that BM/inflammatory cell MKP-1 expression is critical for muscle repair (Fig. 2, A and B). Second, to ascertain the intrinsic contribution of MKP-1 to satellite cell functions, we analyzed the satellite cell progeny of WT and MKP-1−/− single myofibers ex vivo. We found no difference in the number of myofiber-associated satellite cells expressing Pax7 at basal stage or 48 h and Myogenin at 72 h in both genotypes (Fig. S2 D). Furthermore, no differences were observed in the proliferation, differentiation, migration, and fusion rates of cultured WT and MKP-1−/− satellite cells, correlating with a similar p38 activation pattern during the differentiation process (Fig. S2, E–I). Remarkably, addition of conditioned media (CM) from in vitro–activated primary MKP-1−/− macrophages to cultured satellite cells increased their proliferation rate compared with CM from WT macrophages (Fig. S3 A). In contrast, CM from MKP-1−/− macrophages, but not WT CM, reduced the extent of satellite cell differentiation (Fig. S3 B) and fusion (not depicted). Interestingly, these effects were reversed by specific neutralization of the cytokine TNF in MKP-1−/− CM (Fig. S3, A and B), suggesting that the inhibitory actions of MKP-1−/− macrophage-secreted factors on satellite cell functions may be exerted through proinflammatory cytokines.

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