Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype

Angelica Tiotiu; Nazanin Zounemat Kermani; Yusef Badi; Stelios Pavlidis; Philip M Hansbro; Yi-Ke Guo; Kian Fan Chung; Ian M Adcock; U-BIOPRED consortium project team

doi:10.1111/all.14535

Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype

Allergy. 2021 Mar;76(3):775-788. doi: 10.1111/all.14535. Epub 2020 Aug 17.

Authors

Angelica Tiotiu^{1

2}, Nazanin Zounemat Kermani³, Yusef Badi^{1

3}, Stelios Pavlidis^{1

3}, Philip M Hansbro^{4

5}, Yi-Ke Guo³, Kian Fan Chung¹, Ian M Adcock^{1

4}; U-BIOPRED consortium project team

Affiliations

¹ National Heart and Lung Institute, Imperial College London, London, UK.
² Department of Pulmonology, University Hospital of Nancy, Nancy, France.
³ Department of Computing, Data Science Institute, Imperial College London, London, UK.
⁴ Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.
⁵ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.

PMID: 32740964
DOI: 10.1111/all.14535

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.

Keywords: asthma; gene set variation analysis; macrophage subtypes; sputum; tissue-resident.

MeSH terms

Asthma* / diagnosis
Asthma* / genetics
Humans
Macrophage Activation
Macrophages
Phenotype
Sputum*