The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing

Jun et al. Nat Commun. 2015 Jun 16; 6: 7386

Speaker: Yi-Hsin, Hsiao (蕭宜馨)                                Time: 14:10~15:00, Sep. 23, 2015.

Commentator: Jiu-Yao, Wang (王志堯 教授)             Place: Room 601

Abstract:

Neutrophils enter the wound site to remove foreign materials, bacteria and damaged tissue. However, neutrophils must be eliminated, as excessive or persistent neutrophil activity can cause further tissue damage and impede healing. Nowadays, the specific mechanism for neutrophil clearance, the critical process for efficient tissue repair, remains undefined in cutaneous wound healing. Efferocytosis is the process of removal or clearance of apoptotic cells by M2 phenotypes of macrophages. Macrophages may recognize apoptotic cells for efferocytosis through receptors that bind phosphatidylserine (PS), the ‘eat-me’ signal that is exposed on the outer membrane of the lipid bilayer. In this study, the author showed that matricellular protein CCN1 played the key role in neutrophil efferocytosis by acting as a bridging molecule that binds both phosphatidylserine (PS) in senescence neutrophils and integrin α_vβ₃/α_vβ₅ in macrophages to trigger efferocytosis. Knockin mice expressing a mutant CCN1 (Ccn^D125A/+) that is unable to bind α_vβ₃/α_vβ₅ and mice with antisense oligonucleotides Ccn1 knockdown are defective in neutrophil efferocytosis, that even leads to excessive neutrophil accumulation and delayed healing. On the other hand, the supplied with recombinant CCN1-D125A mutant protein inhibits the stimulatory effect of WT CCN1 efferocytosis function in vitro. Besides, treatment of wounds with CCN1 shows the therapeutic to the neutrophil clearance in diabetic Lepr^db/db mice, which suffer from the prolonged inflammation in wounds. These findings suggest us a potential value in the application of CCN1 in certain types of non-healing wounds.

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