Role of nestin/14-3-3/mTOR signaling in airway smooth muscle cell proliferation and airway remodeling

Abstract Airway smooth muscle (ASM) cell proliferation plays a critical role in the progression of asthma. Asthma is characterized by airway remodeling, a cardinal feature of which is aberrant ASM cell proliferation. ASM hyperplasia leads to thickening of the airway wall, which exacerbates airway hyperresponsiveness and narrowing during asthma attacks. Although Th2 cytokines are prominent drivers of asthma pathogenesis, they do not drive ASM hyperplasia in asthma. Here, we discover that nestin, a type VI intermediate filament protein, regulates human ASM cell proliferation via 14-3-3/mechanistic target of rapamycin (mTOR) signaling. More importantly, nestin is upregulated in asthmatic human ASM, an epigenetic effect dependent on ten-eleven translocation methylcytosine dioxygenase 1-mediated 5-hydroxymethylcytosine. Smooth muscle conditional nestin knockout reduces airway smooth muscle thickening, airway hyperresponsiveness, inflammation, and mucus hypersecretion in an allergen-induced murine model of asthma. Moreover, comprehensive in vivo studies demonstrate nestin drives ASM hyperplasia and airway remodeling via 14-3-3/mTOR signaling.