Intracellular concentration of ADA2 is a marker for monocyte differentiation and activation

Abstract

Adenosine, a critical molecule regulating cellular function both inside and outside cells, is controlled by two human adenosine deaminases: ADA1 and ADA2. While ADA1 primarily resides in the cytoplasm, ADA2 can be transported to lysosomes within cells or secreted outside the cell. Patients with ADA2 deficiency (DADA2) often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood. Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages. Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages, and its intracellular concentration decreases in cells secreting TNF-α. This suggests that ADA2 may function as a lysosomal adenosine deaminase, regulating TNF-α expression by the cells. Interestingly, pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage (BAL), correlating with elevated pro-inflammatory cytokine levels. Conversely, cord blood has low ADA2 levels, creating a more immunosuppressive environment. Additionally, secreted ADA2 can bind to apoptotic cells, activating immune cells by reducing extracellular adenosine levels. These findings imply that ADA2 release from monocytes during inflammation, triggered by growth factors, may be crucial for cell activation. Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.

Keywords

adenosine deaminase 2 (ADA2) / TNF-α / adenosine deaminase 2 deficiency (DADA2) / monocyte subsets / macrophage polarization / pneumonia

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Acknowledgements

The authors wish to thank the staff of the Institute of Pediatrics for participating in the study. This work was supported by Guangzhou Women and Children’s Hospital, Guangzhou Science and Technology Project (No. 202201011494 to Liang Dong), and a grant (No. 256053 to Andrey V. Zavialov) from the Finnish Academy.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1110-6 and is accessible to authorized users.

Compliance with ethics guidelines

Conflicts of interest Liang Dong, Bingtai Lu, Wenwen Luo, Xiaoqiong Gu, Chengxiang Wu, Luca Trotta, Mikko Seppanen, Yuxia Zhang, and Andrey V. Zavialov declare that the research was conducted without commercial or financial relationships that could be considered a potential conflict of interest.

The study was undertaken in compliance with the principles of the Helsinki Declaration and was approved by the ethics committee of Helsinki University Central Hospital, Finland. All patients were informed of the study, and they gave written consent before sample collection. The Medical Ethics Committee of Guangzhou Women and Children’s Medical Center (GWCMC) in Guangzhou, China, approved the study of patients with pneumonia under Approval No. 2016111853. The study adhered to ethical standards and guidelines. The serum from cord blood and healthy women was obtained from GWCMC Biobank.

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