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, Boram Kim, Sang Chul Park, Youn Wook Chung, Sung Jae Shin, June‐Yong Lee, Jong 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, Ji-Hwan Ryu, Ji-Hwan Ryu
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. Interstitial macrophages (IM) are a specialised population of macrophage cells in the lungs which regulate lung inflammation. Here using mouse models, the authors show that a CD39+CD9+ IM population reduce IL-23/Th17 driven neutrophilic inflammation through suppression of NETosis.