Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing.
Previous studies showed that cannabinoid 2 (CB2) receptor is expressed in multiple effector cells during skin wound healing. Meanwhile, its functional involvement in inflammation, fibrosis, and cell proliferation in other organs and skin diseases implied CB2 receptor might also regulate skin wound healing. To verify this hypothesis, mice excisional wounds were created and treated with highly selective CB2 receptor agonist GP1a (1-(2,4-dichlorophenyl)-6-methyl- N-piperidin-1-yl-4H-indeno[1,2-c]pyrazole-3-carboxamide) and antagonist AM630 ([6-iodo-2- methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone) respectively. The inflammatory infiltration, cytokine expression, fibrogenesis, and wound re-epithelialization were analyzed. After CB2 receptor activation, neutrophil and macrophage infiltrations were reduced, and expressions of monocyte chemotactic protein (MCP)-1, stromal cell-derived factor (SDF)-1, Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF)-A were decreased. Keratinocyte proliferation and migration were enhanced. Wound re-epithelialization was accelerated. Fibroblast accumulation and fibroblast-to-myofibroblast transformation were attenuated, and expression of pro-collagen I was decreased. Furthermore, HaCaT cells in vitro were treated with GP1a or AM630, which revealed that CB2 receptor activation promoted keratinocyte migration by inducing the epithelial to mesenchymal transition. These results, taken together, indicate that activating CB2 receptor could ameliorate wound healing by reducing inflammation, accelerating re-epithelialization, and attenuating scar formation. Thus, CB2 receptor agonist might be a novel perspective for skin wound therapy.
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Lin-Lin
LL
Wang
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Rui
R
Zhao
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Jiao-Yong
JY
Li
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Shan-Shan
SS
Li
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Min
M
Liu
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Meng
M
Wang
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Meng-Zhou
MZ
Zhang
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Wen-Wen
WW
Dong
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Shu-Kun
SK
Jiang
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Miao
M
Zhang
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China.
Zhi-Ling
ZL
Tian
Institute of Forensic Science, Anshan Municipal People's Procuratorate, Anshan, China.
Chang-Sheng
CS
Liu
Department of Forensic Pathology, China Medical University School of Forensic Medicine, Shenyang, China. Electronic address: dwguan@mail.cmu.edu.cn.
Da-Wei
DW
Guan
D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007192:Indenes / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D062326:Re-Epithelialization / Q000187:drug effects*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
D007192:Indenes; D007211:Indoles; C553580:N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno(1,2-c)pyrazole-3-carboxamide; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D003094:Collagen; C094023:iodopravadoline
AM630 (PubChem CID: 4302963); Cannabinoid 2 receptor; Fibrogenesis; GP1a (PubChem CID: 10252734); Inflammation; Re-epithelialization; Skin wound healing