Monocytes and monocyte-derived macrophages as mediators of sex differences in allergic asthma

Abstract Allergic asthma is a chronic, immune-mediated lung disease mediated that affects more than 200 million people worldwide. Alveolar macrophages (AM) and monocytes are important cellular contributors to asthma. During allergic lung inflammation, AM polarize to a predominantly M2 phenotype. Recruited monocyte-derived macrophages (MDM), rather than resident AM, have been linked to worse allergic lung inflammation by inducing inflammatory cell recruitment, tissue remodeling and lung fibrosis. There are sex differences in the prevalence and severity of asthma. Women have worse symptoms, longer hospital stays, more asthma-related deaths, and they are more refractory to therapy. Here, we wanted to determine if differences in M2 polarization and chemokine receptors by monocytes and MDM from women compared to men could account for sex differences in asthma pathogenesis. We obtained blood monocytes from healthy and asthmatic female and male donors in parallel. We analyzed the expression of chemokine and IL-4/IL-13 receptors, and in M2 macrophage genes in monocytes and MDM stimulated with IL-4 and IL-13. We found robust differences in CCR2, CCR5, and γC between healthy and asthmatic donors. Moreover, we found sex differences in M2 gene expression between asthmatic women and men. Female cells, in general, induced higher M2 gene expression in response to IL-4. Female monocytes expressed more chemokine receptors that would facilitate recruitment to the asthmatic lung. Our findings provide novel insights into how sex affects monocyte and macrophage polarization in asthmatic patients. These sex differences may represent a new therapeutic avenue for managing pathogenic M2 polarization and preventing monocyte recruitment to the allergic lung.