The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis

Abstract

Objective: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement.

Methods: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage.

Results: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs.

Conclusion: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.

Keywords:

• Animal model
• anti-neutrophil cytoplasmic antibody
• microscopic polyangiitis
• neutrophil extracellular traps
• phosphoinositide 3-kinase gamma

Acknowledgements

The authors thank S. Chida for quantification of ROS production; S. Fujita for tissue processing and N. Sato, H. Imagawa, A. Kato, Y. Kadowaki, S. Fukuda, Y. Sugihara, Y. Moribayashi, Y. Kuribayashi, S. Ooi, and K. Yanase for technical support.

Conflict of interest

None.

Additional information

Funding

This work was supported in part by research grants from the Japan Society for the Promotion of Science (JSPS KAKENHI grants JP26461458 and JP15K14947) and the Society for research of lactobacillus (Nyusankin-Kenkyukai) (Yakult Honsha).