Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization
Interleukin-23 regulates interleukin-17 expression in wounds, and its inhibition accelerates diabetic wound healing through the alteration of macrophage polarization
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DOI：
10.1096/fj.201700773r
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发表时间：
2018-04-01
期刊：
影响因子：
4.8
通讯作者：
Khosrotehrani, Kiarash
中科院分区：
文献类型：
--
作者：
Lee, James;Rodero, Mathieu Paul;Khosrotehrani, Kiarash
炎症是皮肤伤口愈合过程中的关键阶段。已知过多的炎症和炎性巨噬细胞会导致伤口闭合和预后受损。这促使我们测试IL-23在IL-17表达中的作用，以及在调节伤口炎症和巨噬细胞极化方面的作用。在多只转基因小鼠背部表面制作4×6 mm的全层创面。肥胖糖尿病小鼠伤口用抗IL-17A、抗IL-23或同型相合抗体治疗。我们发现IL-23-而不是IL-12缺陷的小鼠伤口中IL-17的表达显著减少。这是通过交付重组IL-23来挽救的。IL-23和IL-17缺陷小鼠的非炎症性巨噬细胞显著增加。肥胖糖尿病小鼠经抗IL-17A和抗IL-23p19封闭抗体治疗后，伤口再上皮化明显改善。同样，IL-17(-/-)肥胖小鼠加速伤口闭合，导致iNOS表达减少，炎性巨噬细胞减少，同时维持CD206和淋巴管内皮透明质酸受体1(LYVE1)表达的巨噬细胞。这项研究强调了IL-17途径在伤口闭合中的重要性，为慢性伤口的治疗干预提供了新的可能性。
Inflammation is a critical phase in the healing of skin wounds. Excessive inflammation and inflammatory macrophages are known to cause impaired wound closure and outcome. This prompted us to test the role of IL-23 in IL-17 expression and in modulating wound inflammation and macrophage polarization. Full-thickness wounds (4 x 6 mm) were created on the dorsal surface of multiple genetically modified mouse models. Obese diabetic mouse wounds were treated with anti-IL-17A, anti-IL-23, or isotype-matched antibodies. We found IL-23- but not IL-12-deficient mice displayed significantly reduced IL-17 expression in wounds. This was rescued by delivery of recombinant IL-23. IL-23- and IL-17-deficient mice showed a significant increase in noninflammatory macrophages. Obese diabetic mice treated with anti-IL-17A and anti-IL-23p19 blocking antibodies had significantly improved wound reepithelialization. Similarly, IL-17(-/-) obese mice had accelerated wound closure, resulting in reduced iNOS expression and inflammatory macrophages while maintaining prohealing CD206 and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1)-expressing macrophages. This study highlights the importance of the IL-17 pathway in wound closure offering new possibilities of therapeutic intervention in chronic wounds.