Differential macrophage activation in asthmatic sputum using U-BIOPRED transcriptomics

<b>Background:</b> Macrophages (Mf) are important in controlling both innate and acquired immunity but their role in orchestrating the inflammatory response is severe asthma (SA) remains ill-defined. <b>Aim:</b> We investigated their role by analyzing the expression of Mf gene signatures in sputum transcriptomics from 104 asthma participants and 16 healthy volunteers (HV) of U-BIOPRED cohort. <b>Methods:</b> We used the previously-described transcriptome-analysis clusters (TACs) (Kuo CS, et al. ERJ 2017). Forty-nine differentially activated Mf gene signatures were studied using gene set variation analysis (GSVA) which gave an enrichment score (ES) across severity, TACs and macrophage M1/M2 polarization. ANOVA and adjusted p values were used for statistical analysis. <b>Results:</b> Mf activation was significantly suppressed in SA compared to HV. ES were down-regulated for most Mf subtypes in TAC1 (Th2 phenotype) and TAC2 (non-T2 inflammasome phenotype) vs TAC3 (non-T2 metabolic phenotype) and HV in favor of an up-regulation of immunoregulatory functions involved in Toll-like receptor and TNF receptor/NF-kB activation (all p&lt;0.01). While in TAC1 the eicosanoid biosynthesis via lipoxygenase pathway is upregulated, in TAC2 the inflammasome and interferon pathways are highly expressed (p&lt;0.01). TAC2 is associated with a high expression of M1 macrophages (p&lt;0.01). <b>Conclusions:</b> Mf activation is suppressed in asthmatic compared to HV sputum. However, higher ES were seen for specific Mf subsets in eosinophilic and neutrophilic asthma compared with the greater Mf activation of most subtypes in TAC3 subjects. Targeting the specifically-activated Mf subtypes in different TACs may be an effective therapeutic approach.