Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice.
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.
Khanna
Savita
S
Comprehensive Wound Center, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio, United States of America.
Biswas
Sabyasachi
S
Shang
Yingli
Y
Collard
Eric
E
Azad
Ali
A
Kauh
Courtney
C
Bhasker
Vineet
V
Gordillo
Gayle M
GM
Sen
Chandan K
CK
Roy
Sashwati
S
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
D016207:Cytokines; D053222:Fas Ligand Protein