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

  • Nat Commun. 2024 Oct 4;15(1):8628. doi: 10.1038/s41467-024-53038-2.
Seunghan Han  #  1  2 ,  Bomin Kim  #  1  2 ,  Do Young Hyeon  #  3 ,  Daeun Jeong  1  2 ,  Jaechan Ryu  4 ,  Jae-Sung Nam  5 ,  Yoon Ha Choi  6 ,  Bo-Ram Kim  2  7 ,  Sang Chul Park  8 ,  Youn Wook Chung  1  2 ,  Sung Jae Shin  2  7  9 ,  June-Yong Lee  2  7  9 ,  Jong Kyoung Kim  6 ,  Jihye Park  10 ,  Sei Won Lee  11 ,  Tae-Bum Kim  12 ,  Jae Hee Cheon  10 ,  Hyung-Ju Cho  5 ,  Chang-Hoon Kim  5 ,  Joo-Heon Yoon  13 ,  Daehee Hwang  14 ,  Ji-Hwan Ryu  15  16
Affiliations
  • 1. Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea.
  • 2. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
  • 3. School of Biological Sciences, Seoul National University, Seoul, Korea.
  • 4. Institut Pasteur, Microenvironment and Immunity Unit, Paris, France.
  • 5. Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea.
  • 6. Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea.
  • 7. Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea.
  • 8. Department of Otorhinolaryngology-Head and Neck Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.
  • 9. Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
  • 10. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
  • 11. Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 12. Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 13. Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea. [email protected].
  • 14. School of Biological Sciences, Seoul National University, Seoul, Korea. [email protected].
  • 15. Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea. [email protected].
  • 16. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. [email protected].
  • # Contributed equally.
PMID: 39366998 DOI: 10.1038/s41467-024-53038-2
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.

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