A single-cell atlas of the human respiratory system identifies a monocyte-centered HSPA1B+ inflammatory primed state associated with WTAP

Chronic obstructive pulmonary disease (COPD) is characterized by persistent pulmonary inflammation and tissue remodeling, yet the cellular states and regulatory mechanisms underlying monocyte functional heterogeneity remain incompletely understood. Here, we generate a high-resolution single-cell transcriptomic atlas of the human respiratory system and identify a diverse monocyte functional landscape in healthy lungs containing a HSPA1B + inflammatory monocytes state. This population exhibits enhanced inflammatory programs, cytokine and chemokine activity, and shows a distinct position within the inferred transcriptional landscape of the continuous monocyte functional spectrum. Cell-cell communication analysis further reveals that HSPA1B + inflammatory monocytes function as active communication nodes within a stromal–immune–vascular network, integrating MIF, extracellular matrix, and immune-regulatory signals while mediating CXCL and adhesion-associated interactions with surrounding cellular compartments. Comparative analysis of COPD lung tissues and bronchoalveolar lavage fluid demonstrates selective enrichment of this inflammatory monocyte program in disease-associated environments, whereas peripheral blood monocytes from healthy individuals and COPD patients show limited representation of this state. Integrated transcriptomic and m 6 A regulator-associated analyses identify WTAP, a core component of the m 6 A methyltransferase complex, as a factor associated with the inflammatory monocytes program. WTAP silencing in inflammatory monocyte models suppresses pro-inflammatory mediators while enhancing interferon-response and antigen-presentation programs. Collectively, these findings define an inflammatory monocyte state landscape in the human respiratory system and identify a WTAP-associated transcriptional program linked to monocyte inflammatory activation and functional remodeling in COPD. This study provides new insights into the organization of pulmonary immune states and the potential regulatory mechanisms underlying chronic inflammatory regulation in COPD.