The immunosuppressive effect of the endocannabinoid system on the inflammatory phenotypes of macrophages and mesenchymal
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ARTICLE
The immunosuppressive effect of the endocannabinoid system on the inflammatory phenotypes of macrophages and mesenchymal stromal cells: a comparative study Tim Ruhl1 · Corina Corsten1 · Justus P. Beier1 · Bong‑Sung Kim1,2 Received: 6 July 2020 / Revised: 22 September 2020 / Accepted: 25 September 2020 © Maj Institute of Pharmacology Polish Academy of Sciences 2020
Abstract Background The inflammatory sequence is the first phase of wound healing. Macrophages (MPhs) and mesenchymal stromal cells (MSCs) respond to an inflammatory microenvironment by adapting their functional activity, which polarizes them into the pro-inflammatory phenotypes M1 and MSC1. Prolongation of the inflammatory phase results in the formation of chronic wounds. The endocannabinoid system (ECS) possesses immunomodulatory properties that may impede this cellular phenotypic switch. Methods We investigated the immunosuppressive influence of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on the M1 and MSC1 cytokine secretion. Lipopolysaccharides (LPS) were used as inflammagen to stimulate MPhs and MSCs. Both inflammatory phenotypes were co-exposed to AEA or 2-AG, the specific cannabinoid receptor CB2 agonist JWH-133 served as reference. The inflammatory responses were detected by CD80/163 immuno-labelling and by ELISA measures of secreted IL-6, IL-8, MIF, TNF-α, TGF-β, and VEGF. Results M1 cells were found positive for CD80 expression and secreted less IL-6 and IL-8 than MSC1 cells, while both cell types produced similar amounts of MIF. TNF-α release was increased by M1, and growth factors were secreted by MSC1, only. Cannabinoid receptor ligands efficiently decreased the inflammatory response of M1, while their impact was less pronounced in MSC1. Conclusions The ECS down-regulated the inflammatory responses of MPhs and MSCs by decreasing the cytokine release upon LPS treatment, while CB2 appeared to be of particular importance. Hence, stimulating the ECS by manipulation of endo- or use of exogenous cannabinoids in vivo may constitute a potent therapeutic option against inflammatory disorders. Keywords Macrophage · Mesenchymal stromal cell · Inflammation · Endocannabinoid system · Cytokine
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s43440-020-00166-3) contains supplementary material, which is available to authorized users. * Tim Ruhl [email protected] Corina Corsten corina.corsten@rwth‑aachen.de Justus P. Beier [email protected]
Wound healing can be roughly divided into three sequential and overlapping phases [1]. The immediate response to tissue damage is the inflammatory phase, mainly directed by monocytes and their progeny, macrophages (MPhs). MPhs detect damage and pathogen-associated molecules 1
Department of Plastic Surgery, Hand Surgery–Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
2
Present Address: Department of Plastic and Hand Surgery, University Hospital Zurich, Raemistrasse 100
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