Dectin-2–Mediated Signaling Leads to Delayed Skin Wound Healing through Enhanced Neutrophilic Inflammatory Response and Neutrophil Extracellular Trap Formation

Abstract

Dendritic cell-associated C-type lectin-2 (i.e., dectin-2) recognizes fungal polysaccharides, including a-mannan. Dectin-2emediated recognition of fungi, such as Candida albicans, leads to NF-kB activation, which induces production of inflammatory cytokines. However, the role of dectin-2 in skin wound healing remains unclear. In this study, we sought to determine how dectin-2 deficiency and the administration of a-mannan affected the wound healing process. Full-thickness wounds were created on the backs of wild type C57BL/6 and dectin-2edeficient mice. We analyzed wound closure, histological findings, and re-epithelialization. We also examined the neutrophilic inflammatory responses and neutrophil extracellular trap (NET)-osis at the wound sites after administration of a-mannan. The percent wound closure and re-epithelialization was significantly accelerated in dectin-2eknockout mice compared with wild-type mice on days 3 and 5 after wounding. In contrast, administration of a-mannan delayed wound closure in wild-type mice, and these responses were canceled in dectin-2eknockout mice. Furthermore, mice administered a-mannan, neutrophil infiltration was prolonged, and the expression of citrullinated histone, an indicator of NETosis, at the wound sites was accelerated. Administration of a neutrophil elastase inhibitor significantly improved the delayed wound healing caused by a-mannan. These results suggest that dectin-2 may have a deep impact on the skin wound healing process through regulation of neutrophilic responses.

Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation

“…Accordingly, we examined the effect of neutropenia induced by means of the anti-Gr-1 monoclonal antibody on wound closure and MMP-2 expression. As shown in our recent study [20], the neutrophils in peripheral blood are completely depleted by this treatment. Wound closure on Day 10 was significantly accelerated in anti-Gr-1 antibody-treated mice compared with control IgG-treated mice (Figure 4A).…”

Topical Administration of Heat-Killed Enterococcus faecalis Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing

“…The wounded tissues were fixed with 4% paraformaldehyde-phosphate buffer solution and embedded in paraffin as previously described [ 17 , 18 , 19 ]. Sections were harvested from the central portion of the wound and stained with hematoxylin-eosin (HE) according to the standard method.…”

The emerging roles of neutrophil extracellular traps in wound healing

“…Recent studies on nondiabetic mice have offered new insights into the induction of NET formation during wound healing. Dendritic cell-associated C-type lectin-2 (dectin-2), which is expressed on monocytes, recognizes fungi, activates NF-κB, and induces inflammatory cytokine release [ 92 ]. It has been verified that dectin-2 affects excisional wound healing by regulating the neutrophil inflammatory response and NET formation [ 93 ].…”