Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-04, Vol.11 (9), p.1391
• Main Authors: Suryavanshi, Santosh V, Zaiachuk, Mariia, Pryimak, Nazar, Kovalchuk, Igor, Kovalchuk, Olga
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agents; cannabidiol; Cannabidiol - pharmacology; Cannabinoids; Cannabinoids - pharmacology; Cannabis; Chronic illnesses; Coronaviruses; COVID-19; Cytokine Release Syndrome; Cytokine storm; Cytokines - metabolism; delta-9-tetrahydrocannabinol; Dronabinol - pharmacology; Epithelial cells; Humans; IL-1β; Immune system; Inflammasomes - metabolism; Inflammatory diseases; Interleukin 18; Interleukin 6; Interleukin 8; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Oligomerization; Oxidative stress; Phosphorylation; Protein-tyrosine kinase; Pyrin protein; Signal Transduction; STAT3; Stat3 protein; STAT3 Transcription Factor - metabolism; Tetrahydrocannabinol; Tumor necrosis factor-α; TYK2; TYK2 Kinase - metabolism; TYK2 Kinase - pharmacology; Tyk2 protein
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11091391

Cannabinoids, mainly cannabidiol (CBD) and Δ -tetrahydrocannabinol (THC), are the most studied group of compounds obtained from because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1β (IL-1β) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1β in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation o