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

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 2 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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for western blots.

Article and author information

Author details

  1. Ruchi Roy

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  2. Janet Zayas

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  3. Sunil K Singh

    Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Kaylee Delgado

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Stephen J Wood

    Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  6. Mohamed F Mohamed

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  7. Dulce M Frausto

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  8. Ricardo Estupinian

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  9. Eileena F Giurini

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  10. Timothy M Kuzel

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  11. Andrew Zloza

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  12. Jochen Reiser

    Department of Medicine, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.
  13. Sasha H Shafikhani

    Department of Medicine, Rush University Medical Center, Chicago, United States
    For correspondence
    Sasha_Shafikhani@rush.edu
    Competing interests
    Sasha H Shafikhani, Rush University Medical Center has filed a patent (International Application Number: PCT/US19/41112). Dr. Sasha Shafikhani is the listed inventor on this application..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1755-9997

Funding

National Institutes of Health (RO1DK107713)

  • Sasha H Shafikhani

National Institutes of Health (R01AI150668)

  • Sasha H Shafikhani

National Institutes of Health (F31DK118797)

  • Janet Zayas

National Institutes of Health (GM109421)

  • Janet Zayas

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ursula Rescher, University of Muenster, Germany

Ethics

Animal experimentation: We have an approval from the Rush University Medical Center Institutional Animal Care and Use Committee (IACUC No.: 18-037) to conduct research as indicated. All procedures complied strictly with the standards for care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Academy of Sciences, Bethesda, MD, USA).

Human subjects: We have an Institutional Review Board (IRB)- approved protocol in accordance with the Common Rule (45CFR46, December 13, 2001) and any other governing regulations or subparts. This IRB-approved protocol allows us to collect blood samples from non-diabetic volunteers with their consents for these studies.

Version history

  1. Received: July 9, 2021
  2. Preprint posted: September 11, 2021 (view preprint)
  3. Accepted: February 1, 2022
  4. Accepted Manuscript published: February 3, 2022 (version 1)
  5. Version of Record published: February 15, 2022 (version 2)

Copyright

© 2022, Roy et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ruchi Roy
  2. Janet Zayas
  3. Sunil K Singh
  4. Kaylee Delgado
  5. Stephen J Wood
  6. Mohamed F Mohamed
  7. Dulce M Frausto
  8. Ricardo Estupinian
  9. Eileena F Giurini
  10. Timothy M Kuzel
  11. Andrew Zloza
  12. Jochen Reiser
  13. Sasha H Shafikhani
(2022)
Overriding impaired FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in murine diabetic wound
eLife 11:e72071.
https://doi.org/10.7554/eLife.72071

Share this article

https://doi.org/10.7554/eLife.72071

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