Abstract Chronic obstructive pulmonary disease (COPD) shows greater susceptibility and severity among women, yet the biological basis remains unclear. Toll-like receptor 7 (TLR7), an X-linked sensor of ssRNA, triggers antiviral immunity and may contribute to sex-dependent disease mechanisms. We previously showed that TLR7-deficiency or anti-TLR7 antibody treatment protected against cigarette smoke-induced emphysema and airway remodeling in mice (Liu et al., Nat Commun 2023). However, cell type-specific TLR7 expression patterns and sex differences in COPD remain poorly understood. We quantified TLR7 mRNA by RT-qPCR in lung tissue from never-smokers, smokers without COPD and COPD patients, stratified by sex (n = 106). Female COPD patients showed higher TLR7 expression than males, with a trend toward elevated levels versus female never-smokers, an effect absent in males. Analyses of single-cell RNA-seq data from human lung tissue of severe COPD patients and controls (GSE136831) showed increased TLR7 expression in alveolar macrophages (AMs) from female COPD patients relative to female controls and male COPD patients (Figure 1). Notably, TLR7-signaling genes (IRAK1, IRAK4, TRAF6, MYD88, NFKB1, IRF7, UNC93B1) were upregulated in AMs from female COPD patients, but not in males. CXCL10 was identified among top differentially expressed genes in TLR7+ AMs compared with TLR7- AMs in COPD. To validate this further, we stimulated murine AMs in vitro with TLR7 agonist imiquimod, showing dose-dependent upregulation of Cxcl10. We report the first evidence of female-specific upregulation of TLR7 expression and activation in COPD AMs. These findings support a mechanism contributing to increased COPD susceptibility and severity in women, highlighting TLR7 signaling as a potential therapeutic target. Figure 1: Single-cell RNA-seq data analyses shows an increased expression of TLR7 in alveolar macrophages from female COPD patients relative to female controls and male COPD patients. This abstract is funded by: FWO
Vermaere et al. (Fri,) studied this question.