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

Carmelo Carmona-Rivera, Sami S. Khaznadar, Kyawt Win 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, Peter C. Grayson

Research output: Contribution to journalArticle

1 Citation (Scopus)

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-a. 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.

Original languageEnglish (US)
Pages (from-to)395-406
Number of pages12
JournalBlood
Volume134
Issue number4
DOIs
StatePublished - Jul 25 2019

Fingerprint

Adenosine Deaminase
Adenosine
Macrophages
Neutrophils
Granulocytes
Adenosine A3 Receptor Antagonists
Adenosine A3 Receptors
Adenosine A1 Receptors
NF-kappa B
Adenosine A1 Receptor Antagonists
Reactive Oxygen Species
Deficiency Diseases
Remission Induction
Systemic Vasculitis
Mutation
Genes
Modulation
Extracellular Traps
Severe combined immunodeficiency due to adenosine deaminase deficiency
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Carmona-Rivera, C., Khaznadar, S. S., Shwin, K. W., Irizarry-Caro, J. A., O’Neil, L. J., Liu, Y., ... Grayson, P. C. (2019). Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood, 134(4), 395-406. https://doi.org/10.1182/blood.2018892752

Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. / Carmona-Rivera, Carmelo; Khaznadar, Sami S.; Shwin, Kyawt Win; Irizarry-Caro, Jorge A.; O’Neil, Liam J.; Liu, Yudong; Jacobson, Kenneth A.; Ombrello, Amanda K.; Stone, Deborah L.; Tsai, Wanxia L.; Kastner, Daniel L.; Aksentijevich, Ivona; Kaplan, Mariana J.; Grayson, Peter C.

In: Blood, Vol. 134, No. 4, 25.07.2019, p. 395-406.

Research output: Contribution to journalArticle

Carmona-Rivera, C, Khaznadar, SS, Shwin, KW, Irizarry-Caro, JA, O’Neil, LJ, Liu, Y, Jacobson, KA, Ombrello, AK, Stone, DL, Tsai, WL, Kastner, DL, Aksentijevich, I, Kaplan, MJ & Grayson, PC 2019, 'Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2', Blood, vol. 134, no. 4, pp. 395-406. https://doi.org/10.1182/blood.2018892752
Carmona-Rivera, Carmelo ; Khaznadar, Sami S. ; Shwin, Kyawt Win ; Irizarry-Caro, Jorge A. ; O’Neil, Liam J. ; Liu, Yudong ; Jacobson, Kenneth A. ; Ombrello, Amanda K. ; Stone, Deborah L. ; Tsai, Wanxia L. ; Kastner, Daniel L. ; Aksentijevich, Ivona ; Kaplan, Mariana J. ; Grayson, Peter C. / Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. In: Blood. 2019 ; Vol. 134, No. 4. pp. 395-406.
@article{6f65f608545e46fdb45fa7fdcb66f57a,
title = "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-a. 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.",
author = "Carmelo Carmona-Rivera and Khaznadar, {Sami S.} and Shwin, {Kyawt Win} and Irizarry-Caro, {Jorge A.} and O’Neil, {Liam J.} and Yudong Liu and Jacobson, {Kenneth A.} and Ombrello, {Amanda K.} and Stone, {Deborah L.} and Tsai, {Wanxia L.} and Kastner, {Daniel L.} and Ivona Aksentijevich and Kaplan, {Mariana J.} and Grayson, {Peter C.}",
year = "2019",
month = "7",
day = "25",
doi = "10.1182/blood.2018892752",
language = "English (US)",
volume = "134",
pages = "395--406",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2

AU - Carmona-Rivera, Carmelo

AU - Khaznadar, Sami S.

AU - Shwin, Kyawt Win

AU - Irizarry-Caro, Jorge A.

AU - O’Neil, Liam J.

AU - Liu, Yudong

AU - Jacobson, Kenneth A.

AU - Ombrello, Amanda K.

AU - Stone, Deborah L.

AU - Tsai, Wanxia L.

AU - Kastner, Daniel L.

AU - Aksentijevich, Ivona

AU - Kaplan, Mariana J.

AU - Grayson, Peter C.

PY - 2019/7/25

Y1 - 2019/7/25

N2 - 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-a. 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.

AB - 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-a. 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.

UR - http://www.scopus.com/inward/record.url?scp=85070655702&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070655702&partnerID=8YFLogxK

U2 - 10.1182/blood.2018892752

DO - 10.1182/blood.2018892752

M3 - Article

C2 - 31015188

AN - SCOPUS:85070655702

VL - 134

SP - 395

EP - 406

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -