Cathepsin C orchestrates RSV-induced asthma exacerbation through the dual effect of monocyte-derived macrophages.

Asthma exacerbations (AEs), especially those triggered by respiratory syncytial virus (RSV), remain clinically intractable because of limited treatment options and significant immune heterogeneity. In this study, we investigated the central cellular and molecular mechanisms driving RSV-induced AEs using a house dust mite-sensitized mouse model. Through macrophage depletion, transcriptomic profiling, and pathway inhibition, we identified monocyte-derived macrophages (Mo-Mφs) as key orchestrators of both antiviral responses and inflammatory amplification. Mechanistically, Mo-Mφs upregulate and secrete cathepsin C (CTSC), which in turn activates a previously unrecognized PR3/p38/RELB signaling axis. This axis established a positive feedback loop, sustaining macrophage activation and pathogenic inflammation. Pharmacological inhibition of CTSC disrupted this loop, leading to reduced lung inflammation, mucus hypersecretion, and airway hyperresponsiveness. However, this intervention was accompanied by a measurable compromise in antiviral immunity. This study reveals a previously unrecognized CTSC-driven positive feedback loop in Mo-Mφs as a core pathogenic mechanism underlying RSV-induced AE. These findings identify CTSC as a promising mechanism-based therapeutic target, highlighting the need to carefully balance inflammation control against the preservation of antiviral immunity.