Abstract
Acute Respiratory Distress Syndrome (ARDS) is a life-threatening complication that can ensue following Staphylococcus aureus infection. The enterotoxin produced by these bacteria (SEB) acts as a superantigen thereby activating a large proportion of T cells leading to cytokine storm and severe lung injury. Δ9Tetrahydrocannabinol (THC), a psychoactive ingredient found in Cannabis sativa, has been shown to act as a potent anti-inflammatory agent. In the current study, we investigated the effect of THC treatment on SEB-induced ARDS in mice. While exposure to SEB resulted in acute mortality, treatment with THC led to 100% survival of mice. THC treatment significantly suppressed the inflammatory cytokines, IFN-γ and TNF-α. Additionally, THC elevated the induction of regulatory T cells (Tregs) and their associated cytokines, IL-10 and TGF-β. Moreover, THC caused induction of Myeloid-Derived Suppressor Cells (MDSCs). THC acted through CB2 receptor as pharmacological inhibitor of CB2 receptors blocked the anti-inflammatory effects. THC-treated mice showed significant alterations in the expression of miRNA (miRs) in the lung-infiltrated mononuclear cells (MNCs). Specifically, THC caused downregulation of let7a-5p which targeted SOCS1 and downregulation of miR-34-5p which caused increased expression of FoxP3, NOS1, and CSF1R. Together, these data suggested that THC-mediated alterations in miR expression in the lungs may play a critical role in the induction of immunosuppressive Tregs and MDSCs as well as suppression of cytokine storm leading to attenuation of SEB-mediated lung injury.
Highlights
Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) are caused by a myriad of etiologies such as toxic inhalation, lung contusion, pancreatitis, pneumonia, sepsis, and trauma (Frutos-Vivar et al, 2006)
We investigated if THC would induce anti-inflammatory T regulatory cells (Treg) and Myeloid-Derived Suppressor Cells (MDSCs) in mice exposed to Staphylococcus enterotoxin B (SEB) and if their induction was regulated by miR
SEB acts as a super antigen as it activates a large number of T cells such as those expressing Vb8, triggering cytokine storm, acute toxic shock, and multi-organ failure leading to mortality (Krakauer et al, 2016; Zhang et al, 2017)
Summary
Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) are caused by a myriad of etiologies such as toxic inhalation, lung contusion, pancreatitis, pneumonia, sepsis, and trauma (Frutos-Vivar et al, 2006). Incidence of ARDS in USA is 78.9 per 100,000 persons/year and the mortality rate is 38.5% (Rubenfeld et al, 2005; Rubenfeld and Herridge, 2007). ARDS is triggered by Staphylococcus aureus and its enterotoxin, SEB. SEB acts as a super-antigen by activating a large proportion of T cells expressing certain Vb-specific T cell receptors. Such an activation leads to release of massive amounts of cytokines (Mason et al, 1998) and consequent injury to various organs, including the lungs. ARDS remains difficult to treat and far, no pharmacological protocol is effective in modifying the course of this clinical disorder leading to significant morbidity and mortality (Rubenfeld and Herridge, 2007). Understanding the mechanisms and developing new treatment modalities against ARDS and cytokine storm is timely and critical
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