Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-β signalling.

Hasan Alghetaa,Saurabh Chatterjee,Amira Mohammed,Muthanna Sultan,Philip Busbee,Mitzi Nagarkatti,Prakash Nagarkatti,Angela Murphy

doi:10.1111/jcmm.13542

Hasan Alghetaa, Saurabh Chatterjee + Show 6 more

Open Access

https://doi.org/10.1111/jcmm.13542

Copy DOI

Abstract

Staphylococcal enterotoxin B (SEB) is a potent superantigen produced by Staphylococcus aureus that triggers a strong immune response, characterized by cytokine storm, multi‐organ failure, and often death. When inhaled, SEB can cause acute lung injury (ALI) and respiratory failure. In this study, we investigated the effect of resveratrol (RES), a phytoallexin, on SEB‐driven ALI and mortality in mice. We used a dual‐exposure model of SEB in C3H/HeJ mice, which caused 100% mortality within the first 5 days of exposure, and treatment with RES resulted in 100% survival of these mice up to 10 days post‐SEB exposure. RES reduced the inflammatory cytokines in the serum and lungs, as well as T cell infiltration into the lungs caused by SEB. Treatment with RES also caused increased production of transforming growth factor‐beta (TGF‐β) in the blood and lungs. RES altered the miRNA profile in the immune cells isolated from the lungs. Of these, miR‐193a was strongly induced by SEB and was down‐regulated by RES treatment. Furthermore, transfection studies and pathway analyses revealed that miR‐193a targeted several molecules involved in TGF‐β signalling (TGFβ2, TGFβR3) and activation of apoptotic pathways death receptor‐6 (DR6). Together, our studies suggest that RES can effectively neutralize SEB‐mediated lung injury and mortality through potential regulation of miRNA that promote anti‐inflammatory activities.

Highlights

Acute lung injury (ALI) is an inflammatory respiratory disorder characterized by injury to vascular endothelium and alveolar epithelium from the presence of pulmonary infiltrates which leads to hypoxia.[1]
The lethal nature of staphylococcal enterotoxin B (SEB) is due to the fact that this toxin is a highly potent superantigen, classified as such because of its ability to activate a large proportion of T cells and thereby trigger massive amounts of pro-inflammatory cytokines.[13]
SEB, produced by Gram-positive bacteria S. aureus, is a superantigen because of its ability to activate a large proportion of T cells.[10]

Summary

| INTRODUCTION

Acute lung injury (ALI) is an inflammatory respiratory disorder characterized by injury to vascular endothelium and alveolar epithelium from the presence of pulmonary infiltrates which leads to hypoxia.[1] Many different factors can lead to the development of ALI such as pneumonia, sepsis, age, trauma, smoke, exposure to toxic inhalants like humidifier disinfectants,[2,3] infectious bacteria such as Pseudomonas aerogenosa,[4] opportunistic fungi like Candida albicans[5] and inhalation of bacterial toxins like staphylococcal enterotoxin B (SEB).[6] During the initial infection or injury involving ALI, there is loss of alveolar-capillary membrane integrity resulting in These data suggest that RES may protect SEB-mediated toxicity by decreasing the expression of miR193a, thereby triggering anti-inflammatory pathways

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION