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

the U-BIOPRED consortium project team, Angelica Tiotiu, Nazanin Zounemat Kermani, Yusef Badi, Stelios Pavlidis, Philip M. Hansbro, Yi-Ke GUO, Kian Fan Chung, Ian M. Adcock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)775-788
Number of pages14
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume76
Issue number3
DOIs
Publication statusPublished - Mar 2021

Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

User-Defined Keywords

  • asthma
  • gene set variation analysis
  • macrophage subtypes
  • sputum
  • tissue-resident
  • Phenotype
  • Humans
  • Sputum
  • Macrophages
  • Asthma/diagnosis
  • Macrophage Activation

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