miR-146a-5p Attenuates Allergic Airway Inflammation by Inhibiting the NLRP3 Inflammasome Activation in Macrophages

Abstract

<b><i>Objective:</i></b> Asthma is a common inflammatory respiratory disease with increasing incidence worldwide. This study aimed to investigate the mechanism of miR-146a-5p in reducing allergic airway inflammation by inhibiting NLRP3 inflammasome activation in macrophages. <b><i>Methods:</i></b> Allergic mouse models were established by ovalbumin stimulation, and mice were treated with miR-146a-5p agomir and oe-TIRAP 3 h before OVA stimulation. The pathological changes of lung tissues were observed by hematoxylin-eosin staining. The airway hyperresponsiveness of mice were examined. The miR-146a-5p level was detected by RT-qPCR. The inflammatory cytokines (IL-18/TNF-α) and anti-inflammatory cytokine IL-10 levels in bronchoalveolar lavage fluid and serum IgE levels were examined by ELISA. Airway inflammation in mice was detected after miR-146a-5p overexpression. The levels of NLRP3/ASC/caspase1 proteins and macrophage M1/M2 surface markers in mouse lung tissues were examined using immunohistochemistry, Western blot, and flow cytometry. The targeting relationship between miR-146a-5p and TIRAP was verified by dual-luciferase assay. The p65 levels in the cytoplasm/nucleus of mouse lung tissue were measured. <b><i>Results:</i></b> miR-146a-5p was downregulated in the lung tissues of allergic mice, and miR-146a-5p overexpression alleviated airway inflammation in asthmatic mice. miR-146a-5p suppressed NLRP3 inflammasome activation in macrophages of allergic mice, reduced NLRP3/ASC/caspase1 protein levels in lung tissues, blocked M1 polarization, and promoted M2 polarization. miR-146a-5p targeted TIRAP. TIRAP overexpression partially reversed the promoting effect of miR-146a-5p on M2 polarization. miR-146a-5p can inhibit the activation of the TIRAP/NF-κB pathway. <b><i>Conclusion:</i></b> miR-146a-5p inhibited NLRP3 inflammasome activation in macrophages in the lung tissue of allergic mice, prevented pro-inflammatory phenotype M1 polarization, and promoted anti-inflammatory phenotype M2 polarization by targeting the TIRAP/NF-κB pathway, thus alleviating airway inflammation in allergic asthma.

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

“…Notably, miR-146a-5p-EV treatment exhibited more inhibitory effects on airway inflammation ( Figure 7C ), goblet cell hyperplasia ( Figure 7D ), and collagen fiber content ( Figure 7E ) in chronic asthma mice. In addition, the downstream effector of miR-146a-5p, including TNF receptor-associated factor 6 (TRAF6) ( 35 ) and TIR domain-containing adaptor protein (TIRAP) ( 36 ), which are related to airway epithelial cell injury and airway inflammatory response in asthma, were decreased ( Figure 7F ).…”

Mechanism of KLF9 in airway inflammation in chronic obstructive pulmonary

“…The activation of NLRP3 inflammasome in COPD can be attributed to noxious particles, such as cigarette smoke and PM2.5 5 and such activation may be present in macrophages 44 . NLRP3 inflammasome effectors, IL‐1β and IL‐18, are correlated with COPD‐like symptoms and the disease severity 45 .…”

“…The activation of NLRP3 inflammasome in COPD can be attributed to noxious particles, such as cigarette smoke and PM2.5 5 and such activation may be present in macrophages. 44 NLRP3 inflammasome effectors, IL‐1β and IL‐18, are correlated with COPD‐like symptoms and the disease severity. 45 Moreover, corticosteroids alleviate LPS‐induced inflammation and lung injury by blocking the activation of NLRP3 inflammasome, 46 highlighting that NLRP3 inflammasome can be a drug target for COPD treatment and involves the pathogenesis of COPD, particularly those induced by infection.…”

microRNAs: Critical Players during Helminth Infections

“…In mice, infection by B. malayi induces overexpression of mmu-miR-125b-5p, mmu-miR-146a-5p, and mmu-miR-378-3p in macrophages [ 160 ] ( Figure 3 B). These miRNAs activate macrophages, inflammatory response, and cell–cell communication [ 160 , 161 , 162 ]. For example, mmu-miR-125b-5p is involved in morphological changes during macrophage activation, increasing the expression of co-stimulatory molecules (such as CD80) and INF-γ secretion through the suppression of IFN regulatory factor 4 (IRF4) [ 161 ].…”