Fighting the storm: could novel anti-TNFα and anti-IL-6 C. sativa cultivars tame cytokine storm in COVID-19?

Abstract

The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as ‘cytokine storm’, that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission. Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies. The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis. Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and ‘inflammaging’ - the inflammatory underpinning of aging and frailty.

Inspiration for COVID-19 Treatment: Network Analysis and Experimental Validation of Baicalin for Cytokine Storm

“…TNF-α performed a pivotal role in the CS the same way as IL-6 and might be a major contributor to the increased severity of the disease. Moreover, TNF interaction with TNFR also led to increased expression of other cytokines (IL-6 and IL-1) and chemokines (Menegatti et al, 2019;Kovalchuk et al, 2021). Thereby, regulation of TNF-α production would be a crucial pathway for the prevention and therapy of CS.…”

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses

“…Apart from that, a variety of phytoconstituents present in clinically significant plants appear to have proven immunoregulatory potential in monitoring and maintaining hyperinflammatory responses and are thus being researched for prospective treatment and prevention efficiency in patients with COVID-19 [7,[139][140][141][142][143]. Novel anti-TNF and anti-IL-6 extracts from Cannabis sativa have recently been demonstrated to be useful in regulating the uncontrolled production of inflammatory cytokines [144]. In animal cell lines, C. sativa has been verified to reduce the expression levels of IL-6, IL-8, C-C motif chemokine ligands (CCLs) 2 and 7, and ACE2, suggesting that it may be a valuable contributor to existing anti-inflammatory regimens for the management of COVID-19 [145].…”

Cannabidiol and SARS-CoV-2 Infection

“…Moreover, recent findings highlighted the potential suppressor action of CBD on cytokine production in macrophages ( 45 ). Moreover, CBD can downregulate the expression of COX-2, TNF-α, IL-6, CCL2, and other cytokines in a WI-38 lung fibroblast cell line model with SARS-CoV-2 infection ( 28 ), as observed in a lung epithelial cell model with the decrease in IL-6 and IL-8 secretion ( 29 ) and in intranasal of Poly I:C-induced acute respiratory viral infection of COVID-19 ( 30 ) ( Table 1 ).…”