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

Abstract

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 was observed during active disease in DADA2 and were significantly reduced after remission induction by anti–tumor necrosis factor (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– and peptidylarginine deiminase–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-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB 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.

Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response

“…NET is composed of a decondensed chromatin meshwork imbedded with granule proteins with anti-microbial properties. NET may also work as a physical path for immune cell migration to the inflammatory site ( 34 ). Neutrophil function is impaired in both animal models and humans with aging.…”

Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response

“…This is particularly relevant for infections and other pathological processes that stimulate the formation of neutrophil extracellular traps (NETs), a unique form of cell death in which decondensed chromatin is released into the extracellular environment by activated neutrophils. A recent study reported enhanced NETosis in cells from DADA2 patients, which was linked to increased Ado signaling via adenosine receptors expressed on neutrophils ( 35 ). Thus, it is likely that increased NETosis, subsequent release of cellular DNA coupled, and dysregulated dAdo metabolism in ADA2 patients could synergize to drive innate cytokine responses in DADA2 patients.…”

“…A recent study reported enhanced NETosis in cells from DADA2 patients, which was linked to increased Ado signaling via adenosine receptors expressed on neutrophils (35). Thus, it is likely that increased NETosis, subsequent release of cellular DNA coupled, and dysregulated dAdo metabolism in ADA2 patients could synergize to drive innate cytokine responses in DADA2 patients.…”

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“…Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive monogenic AID caused by ADA2 (formerly known as CECR1) mutations and was first described in 2014 in patients with mild immune deficiency, systemic inflammation, and central nervous system vasculopathy (20). ADA2 deficiency leads to accumulation of adenosine, which then activates neutrophils and dysregulates macrophage differentiation to cause inflammation, damage and fibrosis of many tissues (21). We diagnosed five patients and the median age of onset was 3.2 years old.…”