Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis

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Authors: Seunghan Han ; Bomin Kim ; Do Young Hyeon ; Daeun Jeong ; Jaechan Ryu ; Jae-Sung Nam ; Yoon Ha Choi ; Bo-Ram Kim ; Sang Chul Park ; Youn Wook Chung ; Sung Jae Shin ; June-Yong Lee ; Jong Kyoung Kim ; Jihye Park ; Sei Won Lee ; Tae-Bum Kim ; Jae Hee Cheon ; Hyung-Ju Cho ; Chang-Hoon Kim ; Joo-Heon Yoon ; Daehee Hwang ; Ji-Hwan Ryu

MeSH: Animals ; Antigens, CD ; Apyrase* / metabolism ; Asthma* / immunology ; Asthma* / metabolism ; Extracellular Traps* / immunology ; Extracellular Traps* / metabolism ; Female ; Humans ; Interleukin-23* / immunology ; Interleukin-23* / metabolism ; Lung / immunology ; Lung / pathology ; Macrophages / immunology ; Macrophages / metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neutrophils* / immunology ; Neutrophils* / metabolism ; Tetraspanin 29* / genetics ; Tetraspanin 29* / metabolism ; Th17 Cells* / immunology ; Th17 Cells* / metabolism

Abstract: The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39+CD9+ IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39+CD9+ IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39+CD9+ IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma.