Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Nat Commun. 2024 Oct 4;15(1):8628. doi: 10.1038/s41467-024-53038-2.
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 CD39CD9 interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39CD9 IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39CD9 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 CD39CD9 IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39CD9 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.
IL-23-Th17 轴负责各种炎症性疾病中的中性粒细胞炎症。在这里，我们发现了一种抑制中性粒细胞性哮喘的潜在途径。在我们的中性粒细胞主导性哮喘（NDA）模型中，单细胞 RNA 测序分析确定了一个亚群 CD39CD9 间质巨噬细胞（IMs），其在 NDA 条件下受到 IL-23 的抑制，但在 IL-23 抑制剂 αIL-23p19 的作用下增加。过继转移的 CD39CD9 IMs 抑制中性粒细胞胞外诱捕网形成（NETosis），这是 NDA 的代表性表型，也抑制 Th17 细胞活化和中性粒细胞炎症。CD39CD9 IMs 首先以 CD9 依赖性方式附着于中性粒细胞，然后以 CD39 依赖性方式去除中性粒细胞附近的 ATP，这有助于 NETosis。来自哮喘患者的转录组数据最终显示，严重哮喘患者中 CD39CD9 IMs 减少，而轻度/中度哮喘患者中 CD39CD9 IMs 增加。我们的结果表明，CD39CD9 IMs 通过抑制 IL-23-Th17 轴中的 NETosis 作为中性粒细胞炎症的有效负调节剂发挥作用，因此可以作为 IL-23-Th17 介导的中性粒细胞性哮喘的潜在治疗靶点。
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