期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.72071
关键词
Pseudomonas aeruginosa; wound healing; innate immunity; neutrophils; diabetes; chemotactic response; Mouse
类别
资金
- National Institutes of Health (NIH) [RO1DK107713, R01AI150668, F31DK118797]
- NIH PhD institutional training grant [GM109421]
Infection is a common complication that hinders the healing process in diabetic wounds. Research has found that exposure to glucose impairs chemotaxis signaling in diabetic neutrophils, leading to reduced chemotaxis and delayed migration, making diabetic wounds more susceptible to infection. However, the pro-inflammatory cytokine CCL3 can override the impaired signaling and improve infection control, as well as stimulate healing in diabetic wounds.
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 Lepr(db) (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.
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