MKP-1 coordinates ordered macrophage-phenotype transitions essential for stem cell-dependent tissue repair
Open accessAbstract
Re-establishing tissue homoeostasis in response to injury requires infiltration of inflammatory cells and activation of resident stem cells. However, full tissue recovery also requires that the inflammation is resolved. While it is known that disturbing the interactions between inflammatory cells and tissue resident cells prevents successful healing, the molecular mechanisms underlying the paracrine interactions between these cell types are practically unknown. Here, and in a recent study, we provide mechanistic evidence that macrophages control stem cell-dependent tissue repair. In particular, we found that the temporal spacing of the pro- to anti-inflammatory macrophage polarization switch is controlled by the balance of p38 MAPK (termed here p38) and the MAPK phosphatase MKP-1 during the muscle healing process. Moreover, we demonstrate a new function for MKP-1-regulated p38 signaling in deactivating macrophages during inflammation resolution after injury. Specifically, at advanced stages of regeneration, MKP-1 loss caused an unscheduled "exhaustion-like" state in muscle macrophages, in which neither pro- nor anti-inflammatory cytokines are expressed despite persistent tissue damage, leading to dysregulated reparation by the tissue stem cells. Mechanistically, we demonstrate that p38 and MKP-1 control the AKT pathway through a miR-21-dependent PTEN regulation. Importantly, both genetic and pharmacological interference with the individual components of this pathway restored inflammation-dependent tissue homeostasis in MKP-1-deficient mice and delayed inflammation resolution and tissue repair dysregulation in wild-type mice. Because the process of tolerance to bacterial infection involves a progressive attenuation of pro-inflammatory gene expression, we discuss here the potential similarities between the mechanisms underlying inflammation resolution during tissue repair and those controlling endotoxin tolerance.
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This process leads over some days to a general reduction in cytokine secretion that is probably important for the ultimate resolution of the macrophage phase of wound healing.
“It also leads, over some days, to a general reduction in cytokine secretion that is probably important for the ultimate resolution of the macrophage phase of wound healing.99,100”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
p38 induces miR-21, one of whose targets is PTEN.
“It also induces miR-21, one of whose targets is phosphatase with a tensin motif (PTEN).”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
In macrophages, miR-21 plays a key role in the transition from an inflammatory to an anti-inflammatory phenotype.
“In macrophages, miR-21 plays a key role in the transition from an inflammatory to an anti-inflammatory phenotype.”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
Reduction in PTEN extends the activation of AKT, which turns off the inflammatory state and promotes the anti-inflammatory state.
“The reduction in PTEN extends the activation of protein kinase B (AKT), which turns off the inflammatory state and promotes the anti-inflammatory state.”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
One intracellular signaling pathway controlling the phenotypic switch involves p38 and miR-21.
“One of the intracellular signaling pathways controlling the phenotypic switch involves p38 and miR-21.99,100”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
In a muscle repair system, p38 activity is controlled by MKP-1, which it induces in a feedback loop.
“In a study of a muscle repair system, Perdiguero et al. showed that the activity of p38 is controlled by mitogen-activated kinase phosphatase-1 (MKP-1), which it induces in a feedback loop.99,100”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [99]
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References 64 · Cited by 30
Research works printed but not linked: 1
- Von Knethen AA, Brune B. Delayed activation of PPARgamma by LPS and IFNgamma attenuates the oxidative burst in macrophages. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2001; 15:535-44.
- Authors
- Perdiguero, E., Kharraz, Y., Serrano, A. L., & Muñoz-Cánoves, P.
- Affiliations
- Universitat Pompeu Fabra (ES)
- Corresponding author
- Perdiguero, Eusebio
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2012-03
- Volume
- 11
- Issue
- 5
- Pages
- 877-886
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2088218946
- Cited by
- 30
- References
- 64
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 2 · 2013: 6
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- Muscular Dystrophy Association
- Fundació la Marató de TV3
- Ministerio de Ciencia e Innovación (PLE2009)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- MKP-1, p38 MAPK, macrophage polarization, tissue repair, muscle regeneration, inflammation resolution, Akt signaling, PTEN, miR-21, endotoxin tolerance, paracrine signaling
- MeSH terms
- Animals, Inflammation, Macrophages, Phenotype, Stem Cells, Wound Healing, Signal Transduction, Cyclic AMP Response Element-Binding Protein, Muscle, Skeletal, MicroRNAs, p38 Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Dual Specificity Phosphatase 1
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