Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2

Carmelo Carmona-Rivera, Sami S Khaznadar, Kyawt W Shwin, Jorge A. Irizarry-Caro, Liam J O'Neil, Yudong Liu, Kenneth A. Jacobson, Amanda K Ombrello, Deborah L Stone, Wanxia L Tsai, Daniel L Kastner, Ivona Aksentijevich, Mariana J Kaplan and Peter C Grayson

Key Points

  • Adenosine triggers neutrophil extracellular traps (NETs) via engaging specific adenosine receptors on neutrophils.

  • Genetic deficiency of ADA2 results in enhanced adenosine-mediated NET formation and subsequent TNF production in patients with DADA2.


Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation were observed during active disease in DADA2 and were significantly reduced after remission induction by anti-TNF therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species (ROS)- and peptidylarginine deiminase (PAD)-dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-alpha. Treatment with an A2AAR agonist decreased nuclear translocation of NF-kB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

  • Submitted December 20, 2018.
  • Revision received April 8, 2019.
  • Accepted April 8, 2019.