AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes.
Autophagy is essential in physiological and pathological processes, however, the role of autophagy in cutaneous wound healing and the underlying molecular mechanism remain elusive. We hypothesized that autophagy plays an important role in regulating wound healing. Here, we show that enhanced autophagy negatively impacts on normal cutaneous healing process and is related to chronic wounds as demonstrated by the increased LC3 in diabetic mice skin or patients' chronic wounds. In addition, inhibition of autophagy by 3-MA restores delayed healing in C57BL/6 or db/db mice, demonstrating that autophagy is involved in regulating wound healing. Furthermore, we identify that macrophage is a major cell type underwent autophagy in wounds and increased autophagy induces macrophages polarization into M1 with elevated CD11c population and gene expressions of proinflammatory cytokines. To explore the mechanism underlying autophagy-impaired wound healing, we tested the role of IRF8, a regulator of autophagy, in autophagy-modulated macrophages polarization. IRF8 activation is up-regulating autophagy and M1 polarization of macrophages after AGEs (advanced glycation endproducts) treatment, blocking the IRF8 with shIRF8 inhibits autophagic activity and M1 polarization. In summary, this study elucidates that AGEs induces autophagy and modulates macrophage polarization to M1 via IRF8 activation in impairment of cutaneous wound healing.
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine; Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, China.
Yuanyuan
Y
Guo
Burn and Wound center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Cai
C
Lin
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine; Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, China.
Peng
P
Xu
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine; Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, China.
Shan
S
Wu
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine; Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, China.|Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Xiujun
X
Fu
Burn and Wound center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Weidong
W
Xia
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Institute of Traumatic Medicine; Shanghai Jiao Tong University School of Medicine, Shanghai, 201900, China.|Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Min
M
Yao
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D039521:CD11c Antigen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020123:Sirolimus / Q000633:toxicity; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*; D000099185:Interferon Regulatory Factor-8
D000225:Adenine; D039521:CD11c Antigen; D016207:Cytokines; D017127:Glycation End Products, Advanced; D050835:Interferon Regulatory Factors; D034741:RNA, Small Interfering; D020123:Sirolimus; D000099185:Interferon Regulatory Factor-8; C025946:3-methyladenine