Δ9-Tetrahydrocannabinol Prevents Mortality from Acute Respiratory Distress Syndrome through the Induction of Apoptosis in Immune Cells, Leading to Cytokine Storm Suppression

Amira Mohammed,Nagireddy Putluri,Narendra P Singh,Mitzi Nagarkatti,Guoshuai Cai,Kiesha Wilson,Kathryn Miranda,Hasan F.K Alghetaa,Prakash Nagarkatti

doi:10.3390/ijms21176244

Abstract

Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.

Highlights

Staphylococcal enterotoxin B (SEB) is a superantigen that promotes massive inflammation by triggering a large proportion of T cells expressing certain Vβ T cell receptors [1]
The current study concludes that the treatment of mice with THC post-SEB challenge protects mice from SEB-mediated toxicity by inhibiting inflammation and Acute Respiratory Distress Syndrome (ARDS) through the modulation of miRs targeting mitochondria-related apoptotic genes
Because SEB is a superantigen that drives cytokine storm, our studies revealed that THC is a potent anti-inflammatory agent that has the potential to be used as a therapeutic modality to treat SEB-induced ARDS

Summary

Introduction

Staphylococcal enterotoxin B (SEB) is a superantigen that promotes massive inflammation by triggering a large proportion of T cells expressing certain Vβ T cell receptors [1]. Depending on the route of exposure, SEB can promote toxic responses, leading to food poisoning, toxic shock syndrome, or acute lung injury (ALI). The inhalation of SEB promotes ALI, a life-threatening condition that is characterized by leukocyte infiltration, pro-inflammatory cytokine production, and the breakdown of the lung barrier. In a C3H mouse model, we have previously shown that dual-dose exposure to SEB involving the intranasal route followed by systemic exposure triggers Acute Respiratory Distress Syndrome (ARDS), leading to 100% mortality [2,3]. ARDS can be triggered by infectious agents that trigger a life-threatening condition characterized by severe pulmonary inflammation, poor oxygenation, and respiratory failure [4]. Patients with a severe form of novel coronavirus disease 2019 (COVID-19) were found to exhibit ARDS, cytokine storm, and pulmonary failure [5,6]

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Discussion

Conclusion