MiR-186-5p carried by M2 macrophage-derived exosomes downregulates TRPP2 expression in airway smooth muscle to alleviate asthma progression
Zunyun Wang, Yan Ren, Yicong Li, Yuxin Zhang, Suwen Bai, Wenxuan Hou, Wenjun Zhang, Yanheng Yao, Hongxian Zhao, Minghua Wang, Yumei Luo, Gang Pang, Juan Du
Abstract
• M2-Exos alleviate lung inflammation and airway hyperresponsiveness in asthmatic mice. • M2-Exos target lung inflammation in asthmatic mice. • MiR-186-5p highly expression in M2-Exos to inhibit TRPP2 expression in ASMCs and alleviate airway hyperresponsiveness and inflammation. • MiR-186-5p knock down in M2-Exos lose the ability to regulate TRPP2 and then lose the protective in asthmatic mice. Bronchial asthma (asthma) is a chronic inflammatory disease of the airways that remains an unresolved problem. Reportedly M2 macrophages and exosomes play a role in inflammation, including asthma. We investigated the roles of M2 macrophage-derived exosomes (M2-Exos) effect in asthmatic progression by using ovalbumin (OVA) induced asthmatic mice model. M2-Exos significantly ameliorated the pulmonary inflammatory response and airway hyperresponsiveness in asthmatic mice and suppressed aberrant proliferation and transient receptor potential polycystic protein 2(TRPP2) expression in LPS-stimulated primary airway smooth muscle cells (ASMCs). Then, we found that miR-186-5p of M2-Exos could target TRPP2 through online database analysis. However, miR-186-5p downregulation by miR-186-5p inhibitors decreased the protective effect of M2-Exos in asthmatic mouse and cellular models. miR-186-5p was identified and selectively combined with the polycystin-2 gene encoding TRPP2 protein, inhibited TRPP2 protein production, and downregulated TRPP2 expression. A reduction in the number of TRPP2 calcium (Ca) channels formed on the cell membrane leads to a decreased intracellular Ca 2+ concentration ([Ca 2+ ] i ), causing reduced ASMC contraction and proliferation, thereby improving airway hyperresponsiveness and airway remodeling in asthma. Collectively, we conclude that M2 exosomal miR-186-5p to alleviate asthma progression and airway hyperresponsiveness though downregulating TRPP2 expression. These results may offer a novel insight to the treatment and drug delivery of asthma.