Impaired early neutrophil response and wound closure in diabetic injury is associated with loss of ecrg4 expression

Summary: Abstract Body: Diabetic patients have dysfunctional neutrophil responses that increase their risk of infection and impaired wound healing. We previously demonstrated that Esophageal Cancer Related Gene 4 (ECRG4) regulates early neutrophil recruitment to cutaneous injury through its regulation of neutrophil adhesion receptors and found that loss of ECRG4 results in delayed wound healing and worse infection. Having identified decreased ECRG4 gene expression in diabetic patient leukocytes, we utilized a murine high fat diet (HFD) model of diabetes to evaluate the role of ECRG4 in regulating the inflammatory response to cutaneous injury. Using a full-thickness wound model, we found that HFD mice had delayed wound closure beginning from day 1 post-injury. Evaluation of the early inflammatory response in an aseptic injury model identified impaired neutrophil recruitment in the HFD mice. Neutrophils from HFD mice had decreased surface expression of ECRG4 with increased CD44, similar to ECRG4 KO mice whose neutrophils have increased adhesion receptor expression that impairs early recruitment to injury and infection. Evaluation of neutrophil mobilization from the bone marrow reserves into blood 24 hours after injury demonstrated increased neutrophils in the blood of HFD mice despite decreased recruitment of neutrophils to the site of injury. Ex-vivo functional assessment of HFD mouse neutrophils demonstrated impaired migration to the key end-target chemoattractant, C5a, but increased migration to the intermediate-target chemoattractant CXCL2, suggesting a mechanism for the accumulation of HFD neutrophils in blood but their failure to home to the site of injury. These data indicate that diabetes results in decreased ECRG4 expression, which drives impaired early neutrophil recruitment to the site of injury, with delayed wound healing. Katie D. Pool^{2, 1}, Wooil Choi¹, Gracie J. Hemmat², Robert A. Dorschner² 1. Surgery, University of California San Diego, La Jolla, CA, United States. 2. Dermatology, University of California San Diego, La Jolla, CA, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing