Abstract
Asthma is a chronic inflammatory disease of airways mediated by T-helper 2 (Th2) cells involving complex signaling pathways. Although resveratrol has previously been shown to attenuate allergic asthma, the role of miRNA in this process has not been studied. We investigated the effect of resveratrol on ovalbumin-induced experimental allergic asthma in mice. To that end, BALB/c mice were immunized with ovalbumin (OVA) intraperitoneally followed by oral gavage of vehicle (OVA-veh) or resveratrol (100 mg/kg body) (OVA-res). On day 7, the experimental groups received intranasal challenge of OVA followed by 7 days of additional oral gavage of vehicle or resveratrol. At day 15, all mice were euthanized and bronchioalveolar fluid (BALF), serum and lung infiltrating cells were collected and analyzed. The data showed that resveratrol significantly reduced IL-5, IL-13, and TGF-β in the serum and BALF in mice with OVA-induced asthma. Also, we saw a decrease in CD3+CD4+, CD3+CD8+, and CD4+IL-4+ cells with increase in CD4+CD25+FOXP3+ cells in pulmonary inflammatory cell infiltrate in OVA-res group when compared to OVA-veh. miRNA expression arrays using lung infiltrating cells showed that resveratrol caused significant alterations in miRNA expression, specifically downregulating the expression of miR-34a. Additionally, miR-34a was found to target FOXP3, as evidenced by enhanced expression of FOXP3 in the lung tissue. Also, transfection studies showed that miR-34a inhibitor upregulated FOXP3 expression while miR-34a-mimic downregulated FOXP3 expression. The current study suggests that resveratrol attenuates allergic asthma by downregulating miR-34a that induces increased expression of FOXP3, a master regulator of Treg development and functions.
Highlights
Asthma is a chronic inflammatory condition driven by T-helper 2 (Th2)- immune response characterized by cough, shortness of breath and impairment of lung function which might be life threatening [1]
OVA-veh group showed a significant increase in the levels of IL-5, IL-13, and free active TGF-β in bronchioalveolar fluid (BALF) when compared to the naïve group while these cytokines were significantly lower in BALF of OVA-res group when compared to OVA-veh (Figure 1B)
We looked for percentage of cells expressing CD25+FOXP3+ (Tregs) in the lung infiltrating cells and found that there was significant increase in the percentage of Tregs in resveratrol treated group when compared to vehicle (Figure 2C)
Summary
Asthma is a chronic inflammatory condition driven by T-helper 2 (Th2)- immune response characterized by cough, shortness of breath and impairment of lung function which might be life threatening [1]. One of the disrupted pathways, most often found, comprises of changing the expression of co-stimulatory molecules and cytokines secretion [4]. It is wellknown that asthma and autoimmune diseases with impaired peripheral tolerance are associated with T-regulatory cell dysfunction [6]. T-regs are known to express CD4 and CD25 surface molecules in addition to secretion of anti-inflammatory cytokines represented by IL-10 [8]. The knockdown of FOXP3 results in development of autoimmune diseases in multiple organs due to absence of properly functioning T-regs [10]. Tregs have been found to be defective in both number and function in allergic disease and their mutation has been linked to exaggerated immune response [11,12,13,14,15]
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