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. 2020 Nov 1:260:118424.
doi: 10.1016/j.lfs.2020.118424. Epub 2020 Sep 17.

CB2R agonist JWH-133 attenuates chronic inflammation by restraining M1 macrophage polarization via Nrf2/HO-1 pathway in diet-induced obese mice

Qiong Wu  1 , Yanan Ma  2 , Yang Liu  3 , Ningning Wang  4 , Xin Zhao  5 , Deliang Wen  6
Affiliations

CB2R agonist JWH-133 attenuates chronic inflammation by restraining M1 macrophage polarization via Nrf2/HO-1 pathway in diet-induced obese mice

Qiong Wu et al. Life Sci. .

Erratum in

Abstract

Aims: Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages.

Materials and methods: We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway.

Key findings: We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1β, CC motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride.

Significance: JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity.

Keywords: Cannabinoid receptor type 2; Inflammation; JWH-133; Macrophage polarization; NF-E2-related factor (Nrf2); Obesity.

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