CCR2/CCR5-dependent Lyve1lowMHCIIhigh interstitial macrophages regulate airway inflammation in asthma

<bold>CCR2/CCR5-dependent Lyve1^lowMHCII^high interstitial macrophages regulate airway inflammation in asthma</bold> Lung macrophages comprise heterogeneous populations with diverse biological functions. Based on the tissue localisation, they are broadly categorised into alveolar macrophages (AMs) and interstitial macrophages (IMs), with the latter being much less understood. Recent studies have identified novel IM subsets coexisting in homeostasis, but their role in asthma remains unclear. Using scRNA-seq and flow cytometry, we investigated lung macrophage subsets in a Complete Freud’s Adjuvant (CFA)-house dust mite (HDM)-induced mouse model of severe asthma. We observed a significant decrease in tissue-resident AMs (rAMs), which were replaced by monocyte-derived AMs associated with extracellular matrix (ECM) remodeling. We identified a Lyve1^lowMHCII^high IM subset as the dominant infiltrating immune cell population. This subset showed strong immunoregulatory functions across myeloid and lymphoid cells and originated from classical monocytes with high CCR2/CCR5 expression. Transcriptomic analysis of patients with severe asthma in the U-BIOPRED cohort revealed a corresponding reduction in rAM-associated genes, along with an increase in IM and monocyte-related gene signatures. In the mouse model, dual blockade of CCR2 and CCR5 using the clinically approved drug Cenocriviroc (CVC) significantly reduced lung infiltration of monocytes and Lyve1lowMHCIIhigh IMs, leading to diminished T cell and neutrophil infiltration, reduced inflammatory mediators, and attenuated airway hyperreactivity (AHR). This study uncovers a previously unrecognised pathogenic role for Lyve1^lowMHCII^high IMs in severe asthma and highlights dual CCR2/CCR5 antagonism as a potential therapeutic strategy for treating the disease.