title: Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice.
abstract: BACKGROUND
  Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing.
  
  
  RESULTS
  Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode.
  
  
  CONCLUSIONS
  Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.
authors.affiliation: Comprehensive Wound Center, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio, United States of America.
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Biswas
authors.forename: Yingli
authors.initials: Y
authors.lastname: Shang
authors.forename: Eric
authors.initials: E
authors.lastname: Collard
authors.forename: Ali
authors.initials: A
authors.lastname: Azad
authors.forename: Courtney
authors.initials: C
authors.lastname: Kauh
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhasker
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Gordillo
authors.forename: Chandan K
authors.initials: CK
authors.lastname: Sen
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018384:Oxidative Stress; D012867:Skin / Q000473:pathology; D014945:Wound Healing
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein