Mechanoinflammation: mechanosensing and inflammatory amplification through the airway macrophage Piezo1–NLRP3 axis in cough-variant asthma

Cough-variant asthma (CVA) is characterized by chronic dry cough as its predominant manifestation, lacking the wheezing typical of classic asthma. Violent paroxysmal coughing generates distinct mechanical loads across different airway segments: the larynx and glottis participate in airflow generation; the intrathoracic trachea and main bronchi undergo dynamic compression; bronchial bifurcations and narrowed segments experience elevated wall shear; and distal lung tissue is mainly subjected to volume change and tissue stretch. To address this gap, this review introduces "mechanoinflammation" as a concept-a pathogenic process in which physical forces directly gate mechanosensitive ion channels on immune and structural cells to initiate sterile innate immune cascades and establish self-amplifying inflammatory loops, distinct from the existing concept of "mechanotransduction," which focuses on physiological force-to-signal conversion. Alveolar, interstitial, and inflammation-recruited macrophages occupying different niches may sense corresponding local mechanical changes and together constitute the candidate cellular basis of airway macrophage mechanotransduction. Cough-induced membrane tension may open Piezo1 and mediate calcium influx, which is amplified through the PI3K/AKT axis to license NLRP3 inflammasome assembly and mature IL-1β release. The latter may sensitize vagal C-fiber terminals and may close a physical-immune-neural feedback loop in which coughing initiates inflammation and inflammation reinforces coughing. This signaling axis provides a possible mechanistic explanation for corticosteroid resistance in refractory CVA and provides novel therapeutic directions targeting Piezo1 modulators, NLRP3 inhibitors, and IL-1 blockade to disrupt chronic cough.