Abstract
Neutrophil infiltration constitutes the first step in wound healing, although their timely clearance by macrophage engulfment, or efferocytosis, is critical for efficient tissue repair. However, the specific mechanism for neutrophil clearance in wound healing remains undefined. Here we uncover a key role for CCN1 in neutrophil efferocytosis by acting as a bridging molecule that binds phosphatidylserine, the 'eat-me' signal on apoptotic cells and integrins αvβ3/αvβ5 in macrophages to trigger efferocytosis. Both knockin mice expressing a mutant CCN1 that is unable to bind αvβ3/αvβ5 and mice with Ccn1 knockdown are defective in neutrophil efferocytosis, resulting in exuberant neutrophil accumulation and delayed healing. Treatment of wounds with CCN1 accelerates neutrophil clearance in both Ccn1 knockin mice and diabetic Lepr(db/db) mice, which suffer from neutrophil persistence and impaired healing. These findings establish CCN1 as a critical opsonin in skin injury and suggest a therapeutic potential for CCN1 in certain types of non-healing wounds.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Migration Assays
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Cysteine-Rich Protein 61 / genetics*
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Cysteine-Rich Protein 61 / immunology
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Cysteine-Rich Protein 61 / pharmacology
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Cytophagocytosis / drug effects
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Cytophagocytosis / genetics*
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Cytophagocytosis / immunology
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Diabetes Mellitus / genetics
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Diabetes Mellitus / immunology
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Epidermal Growth Factor / pharmacology
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Fluorescent Antibody Technique
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Humans
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Immunoprecipitation
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Keratinocytes / drug effects
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Macrophages / drug effects
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Macrophages / immunology*
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Mice
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Mice, Inbred C57BL
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Neutrophils / drug effects
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Neutrophils / immunology*
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Real-Time Polymerase Chain Reaction
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Receptors, Leptin / genetics
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Receptors, Vitronectin
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Reverse Transcriptase Polymerase Chain Reaction
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Skin / drug effects
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Skin / immunology
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Skin / injuries*
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Wound Healing / drug effects
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Wound Healing / genetics*
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Wound Healing / immunology
Substances
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CCN1 protein, human
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CCN1 protein, mouse
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Cysteine-Rich Protein 61
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Receptors, Leptin
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Receptors, Vitronectin
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integrin alphaVbeta5
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leptin receptor, mouse
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Epidermal Growth Factor