Infection is a major co-morbidity that contributes to impaired healing in diabetic wounds. Although impairments in diabetic neutrophils have been blamed for this co-morbidity, what causes these impairments and whether they can be overcome, remain largely unclear. Diabetic neutrophils, extracted from diabetic individuals, exhibit chemotaxis impairment but this peculiar functional impairment has been largely ignored because it appears to contradict the clinical findings which blame excessive neutrophil influx (neutrophilia) as a major impediment to healing in chronic diabetic ulcers. Here, we report that exposure to glucose in diabetic range results in impaired chemotaxis signaling through the FPR1 chemokine receptor in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in wound in diabetic animals, and rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary chemokine receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR1 signaling and substantially improves infection control by jumpstarting the neutrophil response toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have real therapeutic potential for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process which is intended to reset chronic ulcers into acute fresh wounds.

中文翻译：

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覆盖糖尿病中性粒细胞中的有缺陷的 FPR 趋化性信号刺激糖尿病伤口的感染控制

感染是导致糖尿病伤口愈合受损的主要合并症。虽然糖尿病中性粒细胞的损伤被归咎于这种合并症，但导致这些损伤的原因以及它们是否可以克服，仍然在很大程度上不清楚。从糖尿病个体中提取的糖尿病中性粒细胞表现出趋化性损伤，但这种特殊的功能性损伤在很大程度上被忽略了，因为它似乎与将中性粒细胞过度流入（中性粒细胞增多）归咎于慢性糖尿病溃疡愈合的主要障碍的临床发现相矛盾。在这里，我们报告暴露于糖尿病范围内的葡萄糖导致通过中性粒细胞中的 FPR1 趋化因子受体的趋化性信号受损，最终导致糖尿病动物伤口中趋化性降低和中性粒细胞运输延迟，并使糖尿病伤口容易感染。我们进一步表明，至少一些辅助趋化因子受体在糖尿病条件下保持功能，并且它们被促炎细胞因子 CCL3 参与，超越了对 FPR1 信号传导的要求，并通过启动中性粒细胞对感染的反应来显着改善感染控制，并刺激糖尿病患者的愈合伤口。我们假设 CCL3 可能具有治疗糖尿病足溃疡的真正治疗潜力，如果它在旨在将慢性溃疡重置为急性新鲜伤口的外科清创过程后局部应用。通过启动中性粒细胞对感染的反应，超越对 FPR1 信号传导的要求，并显着改善感染控制，并刺激糖尿病伤口的愈合。我们假设 CCL3 可能具有治疗糖尿病足溃疡的真正治疗潜力，如果它在旨在将慢性溃疡重置为急性新鲜伤口的外科清创过程后局部应用。通过启动中性粒细胞对感染的反应，超越对 FPR1 信号传导的要求，并显着改善感染控制，并刺激糖尿病伤口的愈合。我们假设 CCL3 可能具有治疗糖尿病足溃疡的真正治疗潜力，如果它在旨在将慢性溃疡重置为急性新鲜伤口的外科清创过程后局部应用。