Δ9 Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells.
BACKGROUND AND PURPOSE:
The superantigen Staphylococcal enterotoxin B (SEB) is a potent activator of Vβ8+T-cells which results in the clonal expansion of ∼30% of the T-cell pool. Consequently, this leads to the substantial release of inflammatory cytokines, induction of toxic shock, and eventually death. In the current study, we investigated if Δ9Tetrahydrocannabinol (THC), a cannabinoid known for its anti-inflammatory properties, could prevent SEB-induced mortality and alleviate symptoms of toxic shock.
We investigated the therapeutic efficacy of THC against the dual administration (intranasal and intraperitoneal) of SEB into C3H/HeJ mice. The effectiveness of THC in mice was determined based on the measurement of numerous SEB-mediated clinical parameters, including production of inflammatory cytokines, immune cell infiltration into the lung, vascular leak, and airway resistance. In addition, the molecular mechanism of action was elucidated in vitro by the activation of splenocytes with SEB.
Exposure to SEB resulted in acute mortality, while THC treatment led to 100% survival of mice. SEB triggered the induction of the miRNA-17-92 cluster, specifically miRNA-18a, which targeted Pten (phosphatase and tensin homolog), an inhibitor the PI3K/Akt signaling pathway, thereby suppressing the induction of T-regulatory cells. In contrast, THC treatment inhibited the individual miRNAs in the cluster, thereby reversing the effects of SEB. Moreover, in its ability to act as a PI3K/Akt inhibitor, THC treatment induced CD4+Foxp3+ T-regulatory cells both in vivo and in vitro, which suppressed cellular proliferation of SEB-activated splenocytes and decreased IFN-γ production.
CONCLUSIONS AND IMPLICATIONS:
We report, for the first time, a role for the miRNA 17-92 cluster in SEB-mediated inflammation. Furthermore, our results suggest that THC is a potent anti-inflammatory compound that may serve as a novel therapeutic to suppress SEB-induced pulmonary inflammation by modulating critical miRNA involved in SEB-induced toxicity and death.
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