Overriding impaired FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in murine diabetic wound

Ruchi Roy, Janet Zayas, Sunil K. Singh, Kaylee Delgado, Stephen J. Wood, Mohamed F. Mohamed, Dulce M. Frausto, Yasmeen A. Albalawi, Thea P. Price, Ricardo Estupinian, Eileena F. Giurini, Timothy M. Kuzel, Andrew Zloza, Jochen Reiser, Sasha H. Shafikhani

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Article numbere72071
JournaleLife
Volume11
DOIs
StatePublished - Feb 2022
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'Overriding impaired FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in murine diabetic wound'. Together they form a unique fingerprint.

Cite this