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

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 () and Ji-Hwan Ryu ()
Additional contact information
Seunghan Han: Yonsei University College of Medicine
Bomin Kim: Yonsei University College of Medicine
Do Young Hyeon: Seoul National University
Daeun Jeong: Yonsei University College of Medicine
Jaechan Ryu: Microenvironment and Immunity Unit
Jae-Sung Nam: Yonsei University College of Medicine
Yoon Ha Choi: Pohang University of Science and Technology
Bo-Ram Kim: Yonsei University College of Medicine
Sang Chul Park: Hallym University College of Medicine
Youn Wook Chung: Yonsei University College of Medicine
Sung Jae Shin: Yonsei University College of Medicine
June-Yong Lee: Yonsei University College of Medicine
Jong Kyoung Kim: Pohang University of Science and Technology
Jihye Park: Yonsei University College of Medicine
Sei Won Lee: University of Ulsan College of Medicine
Tae-Bum Kim: University of Ulsan College of Medicine
Jae Hee Cheon: Yonsei University College of Medicine
Hyung-Ju Cho: Yonsei University College of Medicine
Chang-Hoon Kim: Yonsei University College of Medicine
Joo-Heon Yoon: Yonsei University College of Medicine
Daehee Hwang: Seoul National University
Ji-Hwan Ryu: Yonsei University College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53038-2

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