1. Overriding impaired FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in murine diabetic wound.
- Author
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Roy, Ruchi, Zayas, Janet, Singh, Sunil, Delgado, Kaylee, Wood, Stephen, Mohamed, Mohamed, Frausto, Dulce, Albalawi, Yasmeen, Price, Thea, Estupinian, Ricardo, Giurini, Eileena, Kuzel, Timothy, Zloza, Andrew, Reiser, Jochen, and Shafikhani, Sasha
- Subjects
Pseudomonas aeruginosa ,chemotactic response ,diabetes ,immunology ,inflammation ,innate immunity ,mouse ,neutrophils ,wound healing ,Animals ,Chemokine CCL3 ,Chemotaxis ,Leukocyte ,Diabetes Complications ,Diabetes Mellitus ,Experimental ,Glucose ,Male ,Mice ,Mice ,Inbred C57BL ,Neutrophils ,Receptors ,Formyl Peptide ,Signal Transduction ,Wound Healing ,Wound Infection - Abstract
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, isolated 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 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 formyl peptide receptor (FPR) in neutrophils, culminating in reduced chemotaxis and delayed neutrophil trafficking in the wound of Leprdb (db/db) type two diabetic mice, rendering diabetic wound vulnerable to infection. We further show that at least some auxiliary receptors remain functional under diabetic conditions and their engagement by the pro-inflammatory cytokine CCL3, overrides the requirement for FPR signaling and substantially improves infection control by jumpstarting the neutrophil trafficking toward infection, and stimulates healing in diabetic wound. We posit that CCL3 may have 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.
- Published
- 2022