Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype. Issue 3 (17th August 2020)

• Record Type: Journal Article
• Authors: Tiotiu, Angelica; Zounemat Kermani, Nazanin; Badi, Yusef; Pavlidis, Stelios; Hansbro, Philip M.; Guo, Yi‐Ke; Chung, Kian Fan; Adcock, Ian M.
• Is Part Of: Allergy. Volume 76:Issue 3(2021)
• Page Start: 775
• Page End: 788
• Publication Date: 2020-08-17
• Subjects: asthma -- gene set variation analysis -- macrophage subtypes -- sputum -- tissue‐resident; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.14535
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: Background: Macrophages control innate and acquired immunity, but their role in severe asthma remains ill‐defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U‐BIOPRED cohort. Methods: Forty‐nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue‐resident cells (TR‐Mφ) and two for their polarization (classically and alternatively activated macrophages: M1 and M2, respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome‐associated clusters (TACs). Results: Macrophage numbers were significantly decreased in severe asthma compared to mild‐moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll‐like receptors via NF‐κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL‐2 biosynthesis (all P < .01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll‐like and TNF receptor activation and arachidonic acid metabolism ( P < .001) and in TAC2 for the inflammasome and interferon signalling pathways ( P < .001). Data were validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR‐Mφ were enriched in TAC3 and associated with mitochondrial function. Conclusions: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterized by distinct inflammatory pathways. Abstract : This study investigates gene signature of macrophage phenotypes in sputum of asthmatic and healthy controls. Several specific macrophage subsets identified by gene signatures are highly activated in severe granulocytic asthma and involved distinct inflammatory pathways (eg tumour necrosis factor [TNF] and Toll‐like receptor [TLR] signalling pathways). Macrophage activation and numbers are reduced in severe granulocytic asthma highlighting defective innate immunity. Abbreviations: MMA, mild/moderate asthmatics; SAns, severe asthmatics nonsmokers; SAsm, severe asthmatics smokers; TLR, Toll‐like receptor; TNF, tumor necrosis factor.