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Neutrophils: fast and furious—the nucleotide pathway

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Abstract

Nucleotide signaling is a key element of the neutrophil activation pathway. Neutrophil recruitment and migration to injured tissues is guided by purinergic receptor sensitization, mostly induced by extracellular adenosine triphosphate (ATP) and its hydrolysis product, adenosine (ADO), which is primarily produced by the CD39-CD73 axis located at the neutrophil cell surface. In inflammation unrelated to cancer, neutrophil activation via purinergic signaling aims to eliminate antigens and promote an immune response with minimal damage to healthy tissues; however, an antagonistic response may be expected in tumors. Indeed, alterations in purinergic signaling favor the accumulation of extracellular ATP and ADO in the microenvironment of solid tumors, which promote tumor progression by inducing cell proliferation, angiogenesis, and escape from immune surveillance. Since neutrophils and their N1/N2 polarization spectrum are being considered new components of cancer-related inflammation, the participation of purinergic signaling in pro-tumor activities of neutrophils should also be considered. However, there is a lack of studies investigating purinergic signaling in human neutrophil polarization and in tumor-associated neutrophils. In this review, we discussed the human neutrophil response elicited by nucleotides in inflammation and extrapolated its behavior in the context of cancer. Understanding these mechanisms in cancerous conditions may help to identify new biological targets and therapeutic strategies, particularly regarding tumors that are refractory to traditional chemo- and immunotherapy.

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References

  1. Basanta D, Anderson ARA (2017) Homeostasis Back and Forth: An Ecoevolutionary Perspective of Cancer. Cold Spring Harb Perspect Med 7:a028332. https://doi.org/10.1101/cshperspect.a028332

    Article  PubMed  PubMed Central  Google Scholar 

  2. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature. 454:428–435. https://doi.org/10.1038/nature07201

    Article  CAS  PubMed  Google Scholar 

  3. Lecot P, Sarabi M, Pereira Abrantes M, Mussard J, Koenderman L, Caux C, Bendriss-Vermare N, Michallet M-C (2019) Neutrophil Heterogeneity in Cancer: From Biology to Therapies. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.02155

  4. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature. 420:860–867. https://doi.org/10.1038/nature01322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Donskov F (2013) Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol 23:200–207. https://doi.org/10.1016/j.semcancer.2013.02.001

    Article  CAS  PubMed  Google Scholar 

  6. Dumitru CA, Lang S, Brandau S (2013) Modulation of neutrophil granulocytes in the tumor microenvironment: Mechanisms and consequences for tumor progression. Semin Cancer Biol 23:141–148. https://doi.org/10.1016/j.semcancer.2013.02.005

    Article  CAS  PubMed  Google Scholar 

  7. Grecian R, Whyte MKB, Walmsley SR (2018) The role of neutrophils in cancer. Br Med Bull 128:5–14. https://doi.org/10.1093/bmb/ldy029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang X, Chen D (2018) Purinergic Regulation of Neutrophil Function. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00399

  9. Sadik CD, Kim ND, Luster AD (2011) Neutrophils cascading their way to inflammation. Trends Immunol 32:452–460. https://doi.org/10.1016/j.it.2011.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A (2012) Neutrophil Function: From Mechanisms to Disease. Annu Rev Immunol 30:459–489. https://doi.org/10.1146/annurev-immunol-020711-074942

    Article  CAS  PubMed  Google Scholar 

  11. Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531. https://doi.org/10.1038/nri3024

    Article  CAS  PubMed  Google Scholar 

  12. Giese MA, Hind LE, Huttenlocher A (2019) Neutrophil plasticity in the tumor microenvironment. Blood. 133:2159–2167. https://doi.org/10.1182/blood-2018-11-844548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Patel S, Fu S, Mastio J, Dominguez GA, Purohit A, Kossenkov A, Lin C, Alicea-Torres K, Sehgal M, Nefedova Y, Zhou J, Languino LR, Clendenin C, Vonderheide RH, Mulligan C, Nam B, Hockstein N, Masters G, Guarino M, Schug ZT, Altieri DC, Gabrilovich DI (2018) Unique pattern of neutrophil migration and function during tumor progression. Nat Immunol 19:1236–1247. https://doi.org/10.1038/s41590-018-0229-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dosch M, Gerber J, Jebbawi F, Beldi G (2018) Mechanisms of ATP Release by Inflammatory Cells. Int J Mol Sci 19:1222. https://doi.org/10.3390/ijms19041222

    Article  CAS  PubMed Central  Google Scholar 

  15. Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A, Walk SF, Park D, Woodson RI, Ostankovich M, Sharma P, Lysiak JJ, Harden TK, Leitinger N, Ravichandran KS (2009) Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature. 461:282–286. https://doi.org/10.1038/nature08296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moesta AK, Li X-Y, Smyth MJ (2020) Targeting CD39 in cancer. Nat Rev Immunol 20:739–755. https://doi.org/10.1038/s41577-020-0376-4

    Article  CAS  PubMed  Google Scholar 

  17. Boison D, Yegutkin GG (2019) Adenosine Metabolism: Emerging Concepts for Cancer Therapy. Cancer Cell 36:582–596. https://doi.org/10.1016/j.ccell.2019.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Burnstock G (2041) Introduction to Purinergic Signaling. Methods Mol Biol 2020:1–15. https://doi.org/10.1007/978-1-4939-9717-6_1

    Article  CAS  Google Scholar 

  19. Peleli M, Fredholm BB, Sobrevia L, Carlström M (2017) Pharmacological targeting of adenosine receptor signaling. Mol Asp Med 55:4–8. https://doi.org/10.1016/j.mam.2016.12.002

    Article  CAS  Google Scholar 

  20. Dianzani C, Brunelleschi S, Viano I, Fantozzi R (1994) Adenosine modulation of primed human neutrophils. Eur J Pharmacol 263:223–226. https://doi.org/10.1016/0014-2999(94)90547-9

    Article  CAS  PubMed  Google Scholar 

  21. Fredholm BB, Zhang Y, van der Ploeg I (1996) Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn Schmiedeberg's Arch Pharmacol 354:262–267. https://doi.org/10.1007/BF00171056

    Article  CAS  Google Scholar 

  22. Bazzichi L, Trincavelli L, Rossi A, De Feo F, Lucacchini A, Bombardieri S, Martini C (2005) A2B adenosine receptor activity is reduced in neutrophils from patients with systemic sclerosis. Arthritis Res Ther 7:R189–R195. https://doi.org/10.1186/ar1468

    Article  CAS  PubMed  Google Scholar 

  23. Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG (2006) ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors. Science (80-) 314:1792–1795. https://doi.org/10.1126/science.1132559

    Article  CAS  Google Scholar 

  24. Corriden R, Chen Y, Inoue Y, Beldi G, Robson SC, Insel PA, Junger WG (2008) Ecto-nucleoside Triphosphate Diphosphohydrolase 1 (E-NTPDase1/CD39) Regulates Neutrophil Chemotaxis by Hydrolyzing Released ATP to Adenosine. J Biol Chem 283:28480–28486. https://doi.org/10.1074/jbc.M800039200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gabl M, Winther M, Welin A, Karlsson A, Oprea T, Bylund J, Dahlgren C, Forsman H (2015) P2Y2 receptor signaling in neutrophils is regulated from inside by a novel cytoskeleton-dependent mechanism. Exp Cell Res 336:242–252. https://doi.org/10.1016/j.yexcr.2015.07.014

    Article  CAS  PubMed  Google Scholar 

  26. Önnheim K, Christenson K, Gabl M, Burbiel JC, Müller CE, Oprea TI, Bylund J, Dahlgren C, Forsman H (2014) A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide. Exp Cell Res 323:209–217. https://doi.org/10.1016/j.yexcr.2014.01.023

    Article  CAS  PubMed  Google Scholar 

  27. Nagaoka (2010) Evaluation of the effect of α-defensin human neutrophil peptides on neutrophil apoptosis. Int J Mol Med 26. https://doi.org/10.3892/ijmm_00000544

  28. Sil P, Hayes CP, Reaves BJ, Breen P, Quinn S, Sokolove J, Rada B (2017) P2Y6 Receptor Antagonist MRS2578 Inhibits Neutrophil Activation and Aggregated Neutrophil Extracellular Trap Formation Induced by Gout-Associated Monosodium Urate Crystals. J Immunol 198:428–442. https://doi.org/10.4049/jimmunol.1600766

    Article  CAS  PubMed  Google Scholar 

  29. Pliyev BK, Ivanova AV, Savchenko VG (2014) Extracellular NAD+ inhibits human neutrophil apoptosis. Apoptosis. 19:581–593. https://doi.org/10.1007/s10495-013-0948-x

    Article  CAS  PubMed  Google Scholar 

  30. Vaughan KR, Stokes L, Prince LR, Marriott HM, Meis S, Kassack MU, Bingle CD, Sabroe I, Surprenant A, Whyte MKB (2007) Inhibition of Neutrophil Apoptosis by ATP Is Mediated by the P2Y 11 Receptor. J Immunol 179:8544–8553. https://doi.org/10.4049/jimmunol.179.12.8544

    Article  CAS  PubMed  Google Scholar 

  31. Wang X, Qin W, Xu X, Xiong Y, Zhang Y, Zhang H, Sun B (2017) Endotoxin-induced autocrine ATP signaling inhibits neutrophil chemotaxis through enhancing myosin light chain phosphorylation. Proc Natl Acad Sci 114:4483–4488. https://doi.org/10.1073/pnas.1616752114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Karmakar M, Katsnelson MA, Dubyak GR, Pearlman E (2016) Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat Commun 7:10555. https://doi.org/10.1038/ncomms10555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pandolfi F, Altamura S, Frosali S, Conti P (2016) Key Role of DAMP in Inflammation, Cancer, and Tissue Repair. Clin Ther 38:1017–1028. https://doi.org/10.1016/j.clinthera.2016.02.028

    Article  CAS  PubMed  Google Scholar 

  34. Allard D, Chrobak P, Allard B, Messaoudi N, Stagg J (2019) Targeting the CD73-adenosine axis in immuno-oncology. Immunol Lett 205:31–39. https://doi.org/10.1016/j.imlet.2018.05.001

    Article  CAS  PubMed  Google Scholar 

  35. Giuliani AL, Sarti AC, Di Virgilio F (2020) Ectonucleotidases in Acute and Chronic Inflammation. Front Pharmacol 11:619458. https://doi.org/10.3389/fphar.2020.619458

    Article  CAS  PubMed  Google Scholar 

  36. Ponzetta A, Carriero R, Carnevale S, Barbagallo M, Molgora M, Perucchini C, Magrini E, Gianni F, Kunderfranco P, Polentarutti N, Pasqualini F, Di Marco S, Supino D, Peano C, Cananzi F, Colombo P, Pilotti S, Alomar SY, Bonavita E, Galdiero MR, Garlanda C, Mantovani A, Jaillon S (2019) Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors. Cell 178:346–360.e24. https://doi.org/10.1016/j.cell.2019.05.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Si Y, Merz SF, Jansen P, Wang B, Bruderek K, Altenhoff P, Mattheis S, Lang S, Gunzer M, Klode J, Squire A, Brandau S (2019) Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue. Sci Immunol 4:eaaw9159. https://doi.org/10.1126/sciimmunol.aaw9159

    Article  CAS  PubMed  Google Scholar 

  38. Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A (2020) Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer 20:485–503. https://doi.org/10.1038/s41568-020-0281-y

    Article  CAS  PubMed  Google Scholar 

  39. Zhou J, Nefedova Y, Lei A, Gabrilovich D (2018) Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells. Semin Immunol 35:19–28. https://doi.org/10.1016/j.smim.2017.12.004

    Article  CAS  PubMed  Google Scholar 

  40. Di Virgilio F, Vuerich M (2015) Purinergic signaling in the immune system. Auton Neurosci 191:117–123. https://doi.org/10.1016/j.autneu.2015.04.011

    Article  CAS  PubMed  Google Scholar 

  41. Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I (2011) Adenosinergic Regulation of the Expansion and Immunosuppressive Activity of CD11b + Gr1 + Cells. J Immunol 187:6120–6129. https://doi.org/10.4049/jimmunol.1101225

    Article  CAS  PubMed  Google Scholar 

  42. Bao Y, Ledderose C, Seier T, Graf AF, Brix B, Chong E, Junger WG (2014) Mitochondria Regulate Neutrophil Activation by Generating ATP for Autocrine Purinergic Signaling. J Biol Chem 289:26794–26803. https://doi.org/10.1074/jbc.M114.572495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li X, Kondo Y, Bao Y, Staudenmaier L, Lee A, Zhang J, Ledderose C, Junger WG (2017) Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis. Crit Care Med 45:e97–e104. https://doi.org/10.1097/CCM.0000000000002052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. De Marchi E, Orioli E, Pegoraro A, Sangaletti S, Portararo P, Curti A, Colombo MP, Di Virgilio F, Adinolfi E (2019) The P2X7 receptor modulates immune cells infiltration, ectonucleotidases expression and extracellular ATP levels in the tumor microenvironment. Oncogene. 38:3636–3650. https://doi.org/10.1038/s41388-019-0684-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. del Rey A, Renigunta V, Dalpke AH, Leipziger J, Matos JE, Robaye B, Zuzarte M, Kavelaars A, Hanley PJ (2006) Knock-out Mice Reveal the Contributions of P2Y and P2X Receptors to Nucleotide-induced Ca2+ Signaling in Macrophages. J Biol Chem 281:35147–35155. https://doi.org/10.1074/jbc.M607713200

    Article  CAS  PubMed  Google Scholar 

  46. Adinolfi E, De Marchi E, Orioli E, Pegoraro A, Di Virgilio F (2019) Role of the P2X7 receptor in tumor-associated inflammation. Curr Opin Pharmacol 47:59–64. https://doi.org/10.1016/j.coph.2019.02.012

    Article  CAS  PubMed  Google Scholar 

  47. Vijayan D, Young A, Teng MWL, Smyth MJ (2017) Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17:709–724. https://doi.org/10.1038/nrc.2017.86

    Article  CAS  PubMed  Google Scholar 

  48. Li X-Y, Moesta AK, Xiao C, Nakamura K, Casey M, Zhang H, Madore J, Lepletier A, Aguilera AR, Sundarrajan A, Jacoberger-Foissac C, Wong C, dela Cruz T, Welch M, Lerner AG, Spatola BN, Soros VB, Corbin J, Anderson AC, Effern M, Hölzel M, Robson SC, Johnston RL, Waddell N, Smith C, Bald T, Geetha N, Beers C, Teng MWL, Smyth MJ (2019) Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity. Cancer Discov 9:1754–1773. https://doi.org/10.1158/2159-8290.CD-19-0541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yan J, Li X-Y, Roman Aguilera A, Xiao C, Jacoberger-Foissac C, Nowlan B, Robson SC, Beers C, Moesta AK, Geetha N, Teng MWL, Smyth MJ (2020) Control of Metastases via Myeloid CD39 and NK Cell Effector Function. Cancer Immunol Res 8:356–367. https://doi.org/10.1158/2326-6066.CIR-19-0749

    Article  CAS  PubMed  Google Scholar 

  50. Chen Y, Yao Y, Sumi Y, Li A, U.K. To, Elkhal A, Inoue Y, Woehrle T, Zhang Q, Hauser C, Junger WG (2010) Purinergic Signaling: A Fundamental Mechanism in Neutrophil Activation. Sci Signal 3:ra45. https://doi.org/10.1126/scisignal.2000549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kukulski F, Ben Yebdri F, Lefebvre J, Warny M, Tessier PA, Sévigny J (2007) Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo. J Leukoc Biol 81:1269–1275. https://doi.org/10.1189/jlb.1206758

    Article  PubMed  Google Scholar 

  52. Kukulski F, Ben Yebdri F, Lecka J, Kauffenstein G, Lévesque SA, Martín-Satué M, Sévigny J (2009) Extracellular ATP and P2 receptors are required for IL-8 to induce neutrophil migration. Cytokine. 46:166–170. https://doi.org/10.1016/j.cyto.2009.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kukulski F, Ben Yebdri F, Bahrami F, Fausther M, Tremblay A, Sévigny J (2010) Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro. Mol Immunol 47:991–999. https://doi.org/10.1016/j.molimm.2009.11.020

    Article  CAS  PubMed  Google Scholar 

  54. Braganhol E, Kukulski F, Lévesque SA, Fausther M, Lavoie EG, Zanotto-Filho A, Bergamin LS, Pelletier J, Bahrami F, Ben Yebdri F, Fonseca Moreira JC, Battastini AMO, Sévigny J (2015) Nucleotide receptors control IL-8/CXCL8 and MCP-1/CCL2 secretions as well as proliferation in human glioma cells. Biochim Biophys Acta Mol basis Dis 1852:120–130. https://doi.org/10.1016/j.bbadis.2014.10.014

    Article  CAS  Google Scholar 

  55. Kukulski F, Bahrami F, Ben Yebdri F, Lecka J, Martín-Satué M, Lévesque SA, Sévigny J (2011) NTPDase1 Controls IL-8 Production by Human Neutrophils. J Immunol 187:644–653. https://doi.org/10.4049/jimmunol.1002680

    Article  CAS  PubMed  Google Scholar 

  56. Rose FR, Hirschhorn R, Weissmann G, Cronstein BN (1988) Adenosine promotes neutrophil chemotaxis. J Exp Med 167:1186–1194. https://doi.org/10.1084/jem.167.3.1186

    Article  CAS  PubMed  Google Scholar 

  57. Perrot I, Michaud H-A, Giraudon-Paoli M, Augier S, Docquier A, Gros L, Courtois R, Déjou C, Jecko D, Becquart O, Rispaud-Blanc H, Gauthier L, Rossi B, Chanteux S, Gourdin N, Amigues B, Roussel A, Bensussan A, Eliaou J-F, Bastid J, Romagné F, Morel Y, Narni-Mancinelli E, Vivier E, Paturel C, Bonnefoy N (2019) Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies. Cell Rep 27:2411–2425.e9. https://doi.org/10.1016/j.celrep.2019.04.091

    Article  CAS  PubMed  Google Scholar 

  58. Németh T, Sperandio M, Mócsai A (2020) Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov 19:253–275. https://doi.org/10.1038/s41573-019-0054-z

    Article  CAS  PubMed  Google Scholar 

  59. Richer BC, Salei N, Laskay T, Seeger K (2018) Changes in Neutrophil Metabolism upon Activation and Aging. Inflammation. 41:710–721. https://doi.org/10.1007/s10753-017-0725-z

    Article  CAS  PubMed  Google Scholar 

  60. Shaul ME, Levy L, Sun J, Mishalian I, Singhal S, Kapoor V, Horng W, Fridlender G, Albelda SM, Fridlender ZG (2016) Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology 5:e1232221. https://doi.org/10.1080/2162402X.2016.1232221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Grassi F (2010) Purinergic Control of Neutrophil Activation. J Mol Cell Biol 2:176–177. https://doi.org/10.1093/jmcb/mjq014

    Article  CAS  PubMed  Google Scholar 

  62. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, Kepp O, Métivier D, Galluzzi L, Perfettini J-L, Zitvogel L, Kroemer G (2014) Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 21:79–91. https://doi.org/10.1038/cdd.2013.75

    Article  CAS  PubMed  Google Scholar 

  63. Campos-Contreras A d R, Díaz-Muñoz M, Vázquez-Cuevas FG (2020) Purinergic Signaling in the Hallmarks of Cancer. Cells 9:1612. https://doi.org/10.3390/cells9071612

    Article  CAS  PubMed Central  Google Scholar 

  64. Mehta VB, Hart J, Wewers MD (2001) ATP-stimulated Release of Interleukin (IL)-1β and IL-18 Requires Priming by Lipopolysaccharide and Is Independent of Caspase-1 Cleavage. J Biol Chem 276:3820–3826. https://doi.org/10.1074/jbc.M006814200

    Article  CAS  PubMed  Google Scholar 

  65. Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F (2018) The P2X7 receptor: A main player in inflammation. Biochem Pharmacol 151:234–244. https://doi.org/10.1016/j.bcp.2017.12.021

    Article  CAS  PubMed  Google Scholar 

  66. Amoroso F, Capece M, Rotondo A, Cangelosi D, Ferracin M, Franceschini A, Raffaghello L, Pistoia V, Varesio L, Adinolfi E (2015) The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma. Oncogene. 34:5240–5251. https://doi.org/10.1038/onc.2014.444

    Article  CAS  PubMed  Google Scholar 

  67. De Marchi E, Orioli E, Dal Ben D, Adinolfi E (2016) P2X7 Receptor as a Therapeutic Target. pp. 39–79. https://doi.org/10.1016/bs.apcsb.2015.11.004

  68. Di Virgilio F, Sarti AC, Falzoni S, De Marchi E, Adinolfi E (2018) Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 18:601–618. https://doi.org/10.1038/s41568-018-0037-0

    Article  CAS  PubMed  Google Scholar 

  69. Bou Ghanem EN, Clark S, Roggensack SE, McIver SR, Alcaide P, Haydon PG, Leong JM (2015) Extracellular Adenosine Protects against Streptococcus pneumoniae Lung Infection by Regulating Pulmonary Neutrophil Recruitment. PLoS Pathog 11:e1005126. https://doi.org/10.1371/journal.ppat.1005126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Amulic B, Sollberger G (2018) Why Immune Cells Extrude Webs of DNA and Protein. NETS: two faced players in Immunity. Science 33:44–51

    Google Scholar 

  71. Sorvillo N, Cherpokova D, Martinod K, Wagner DD (2019) Extracellular DNA NET-Works With Dire Consequences for Health. Circ Res 125:470–488. https://doi.org/10.1161/CIRCRESAHA.119.314581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hurt B, Schulick R, Edil B, El Kasmi KC, Barnett C (2017) Cancer-promoting mechanisms of tumor-associated neutrophils. Am J Surg 214:938–944. https://doi.org/10.1016/j.amjsurg.2017.08.003

    Article  PubMed  Google Scholar 

  73. Galdiero MR, Varricchi G, Loffredo S, Mantovani A, Marone G (2018) Roles of neutrophils in cancer growth and progression. J Leukoc Biol 103:457–464. https://doi.org/10.1002/JLB.3MR0717-292R

    Article  CAS  PubMed  Google Scholar 

  74. Loffredo S, Borriello F, Iannone R, Ferrara AL, Galdiero MR, Gigantino V, Esposito P, Varricchi G, Lambeau G, Cassatella MA, Granata F, Marone G (2017) Group V Secreted Phospholipase A2 Induces the Release of Proangiogenic and Antiangiogenic Factors by Human Neutrophils. Front Immunol 8. https://doi.org/10.3389/fimmu.2017.00443

  75. Martel-Gallegos G, Rosales-Saavedra MT, Reyes JP, Casas-Pruneda G, Toro-Castillo C, Pérez-Cornejo P, Arreola J (2010) Human neutrophils do not express purinergic P2X7 receptors. Purinergic Signal 6:297–306. https://doi.org/10.1007/s11302-010-9178-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Park J, Wysocki RW, Amoozgar Z, Maiorino L, Fein MR, Jorns J, Schott AF, Kinugasa-Katayama Y, Lee Y, Won NH, Nakasone ES, Hearn SA, Kuttner V, Qiu J, Almeida AS, Perurena N, Kessenbrock K, Goldberg MS, Egeblad M (2016) Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci Transl Med 8:361ra138. https://doi.org/10.1126/scitranslmed.aag1711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rayes RF, Mouhanna JG, Nicolau I, Bourdeau F, Giannias B, Rousseau S, Quail D, Walsh L, Sangwan V, Bertos N, Cools-Lartigue J, Ferri LE, Spicer JD (2019) Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effects. JCI Insight 4. https://doi.org/10.1172/jci.insight.128008

  78. Arpinati L, Shaul ME, Kaisar-Iluz N, Mali S, Mahroum S, Fridlender ZG (2020) NETosis in cancer: a critical analysis of the impact of cancer on neutrophil extracellular trap (NET) release in lung cancer patients vs. mice. Cancer Immunol Immunother 69:199–213. https://doi.org/10.1007/s00262-019-02474-x

    Article  CAS  PubMed  Google Scholar 

  79. Berger-Achituv S, Brinkmann V, Abed UA, Kühn LI, Ben-Ezra J, Elhasid R, Zychlinsky A (2013) A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol 4. https://doi.org/10.3389/fimmu.2013.00048

  80. Perisanidis C, Kornek G, Pöschl PW, Holzinger D, Pirklbauer K, Schopper C, Ewers R (2013) High neutrophil-to-lymphocyte ratio is an independent marker of poor disease-specific survival in patients with oral cancer. Med Oncol 30:334. https://doi.org/10.1007/s12032-012-0334-5

    Article  CAS  PubMed  Google Scholar 

  81. Xiao W-K, Chen D, Li S-Q, Fu S-J, Peng B-G, Liang L-J (2014) Prognostic significance of neutrophil-lymphocyte ratio in hepatocellular carcinoma: a meta-analysis. BMC Cancer 14:117. https://doi.org/10.1186/1471-2407-14-117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhao J, Pan K, Wang W, Chen J, Wu Y, Lv L, Li J, Chen Y, Wang D, Pan Q, Li X, Xia J (2012) The Prognostic Value of Tumor-Infiltrating Neutrophils in Gastric Adenocarcinoma after Resection. PLoS One 7:e33655. https://doi.org/10.1371/journal.pone.0033655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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. 134:395–406. https://doi.org/10.1182/blood.2018892752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xu K, Cooney KA, Shin EY, Wang L, Deppen JN, Ginn SC, Levit RD (2019) Adenosine from a biologic source regulates neutrophil extracellular traps (NETs). J Leukoc Biol 105:1225–1234. https://doi.org/10.1002/JLB.3VMA0918-374R

    Article  CAS  PubMed  Google Scholar 

  85. Mestas J, Hughes CCW (2004) Of Mice and Not Men: Differences between Mouse and Human Immunology. J Immunol 172:2731–2738. https://doi.org/10.4049/jimmunol.172.5.2731

    Article  CAS  PubMed  Google Scholar 

  86. Wiesner O, Litwiller RD, Hummel AM, Viss MA, McDonald CJ, Jenne DE, Fass DN, Specks U (2005) Differences between human proteinase 3 and neutrophil elastase and their murine homologues are relevant for murine model experiments. FEBS Lett 579:5305–5312. https://doi.org/10.1016/j.febslet.2005.08.056

    Article  CAS  PubMed  Google Scholar 

  87. Stackowicz J, Jönsson F, Reber LL (2020) Mouse Models and Tools for the in vivo Study of Neutrophils. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.03130

  88. Sugawara T, Miyamoto M, Takayama S, Kato M (1995) Separation of neutrophils from blood in human and laboratory animals and comparison of the chemotaxis. J Pharmacol Toxicol Methods 33:91–100. https://doi.org/10.1016/1056-8719(94)00062-9

    Article  CAS  PubMed  Google Scholar 

  89. Soroush F, Tang Y, Mustafa O, Sun S, Yang Q, Kilpatrick LE, Kiani MF (2020) Neutrophil-endothelial interactions of murine cells is not a good predictor of their interactions in human cells. FASEB J 34:2691–2702. https://doi.org/10.1096/fj.201900048R

    Article  CAS  PubMed  Google Scholar 

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Funding

The authors would like to thank the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS; process number 19/2551-0000663-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; code 001), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq –process numbers 312187/2018-1; 400882/2019-1), Hospital de Clínicas de Porto Alegre (FIPE process number 2019–0446), Santa Casa de Misericórdia de Porto Alegre, and Universidade Federal de Ciências da Saúde de Porto Alegre. D.S. Rubenich, P.O. de Souza, N. Omizzollo, G.S. Lenz, and E. Braganhol are recipients of UFCSPA, FAPERGS, CAPES, and CNPq fellowships.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Sarmento Leite St, 245 – Main Building – Room 304, Porto Alegre, RS, 90.050-170, Brazil

    Dominique S. Rubenich, Priscila O. de Souza, Natalia Omizzollo, Gabriela S. Lenz & Elizandra Braganhol

  2. Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária do Instituto de Cardiologia (IC-FUC), Porto Alegre, RS, Brazil

    Dominique S. Rubenich, Natalia Omizzollo, Gabriela S. Lenz & Elizandra Braganhol

  3. Département de Microbiologie-infectiologie et d’Immunologie, Faculté de Médecine, Université Laval, QC, Québec, Canada

    Jean Sevigny

  4. Centre de Recherchedu CHU de Québec, Université Laval, Québec City, QC, G1V4G2, Canada

    Jean Sevigny

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  1. Dominique S. Rubenich
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  2. Priscila O. de Souza
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  3. Natalia Omizzollo
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  4. Gabriela S. Lenz
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  6. Elizandra Braganhol
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Correspondence to Elizandra Braganhol.

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Highlights

1. Activation and upregulation of the purinergic system could favor pro-tumor neutrophil activity.

2. Purinergic receptors P2Y2, A2a, and A3 guide neutrophil migration through an ATP concentration gradient, TLR4 stimulation, or IL-8 secretion.

3. Neutrophil migration to injured sites is impaired by the decrease in extracellular adenosine levels mediated by CD73 inhibition.

4. Extracellular adenosine plays a key role in NET production via A1 and A3 receptor sensitization.

5. P2Y6 signaling upregulates the Bcl-xl-mediated anti-apoptotic pathway and inhibits neutrophil apoptosis.

Glossary

A2

α-2 adrenergic G-protein-coupled receptor.

A1/A2a/A2b/A3

P1 purinergic receptors sensitized by adenosine.

ADO

Adenosine is a purine nucleoside that participates in the purinergic system as a form of extracellular signaling, modulating proliferation, differentiation, cell death, and control of inflammatory response events, acting mainly as an immunosuppressive/immunomodulatory molecule via P1 receptor sensitization.

ADP

Adenosine diphosphate is a nucleotide that also participates in the purinergic system as a form of extracellular signaling, inducing platelet aggregation and microglial migration via P2Y12 sensitization.

AMP

Adenosine monophosphate is a nucleotide formed in the extracellular environment mainly via ATP hydrolysis mediated by NTPDase1/CD39 enzyme activity. Until now, no purine-receptor has been described to be activated by this nucleotide.

ATP

Adenosine triphosphate is a purine nucleotide involved in complex signaling pathways, including driving energy to the cells and being a precursor to DNA and RNA. In this case, it participates in the purinergic system, a form of extracellular signaling via the P2 receptor agonist.

NTPDase1/CD39

Ecto-nucleoside triphosphate diphosphohydrolase-1 is an enzyme located at the cell surface of immune cells and some cancer cells that hydrolyze the P2 receptor ligands ATP, ADP, UTP, and UDP to the respective monophosphate-nucleosides by removing one phosphate at a time.

CD73

Ecto-5’-nucleotidase is an enzyme present on the cell surface of a large number of tissues that is responsible for converting AMP to ADO in the purinergic system. It also acts as a cell-cell and cell-matrix protein, important for cell communication and migration, by potentiating EGFR/Akt and VEGF/Akt pathways. In addition, it promotes invasion, migration, and adhesion of tumor cells.

HIF1α

Hypoxia-inducible factor 1-alpha. It is a transcriptional regulator of cellular and developmental response to hypoxia.

HNP-1

Human neutrophil peptide 1 belonging to the α-defensin family of antimicrobial peptides.

IL-8

Interleukin-8, a chemokine released by macrophages and other cells of the innate immune response that attracts neutrophils and other immune cells to the tumor or infection site. It is also involved in angiogenesis, cell proliferation, and tissue remodeling.

LPS

Lipopolysaccharide is a large molecule made of a lipid and a polysaccharide that occurs in the membrane of Gram-negative bacteria, acting as a trigger for the innate immune system; it is classified as a PAMP (pathogen-associated molecular pattern).

N1

Neutrophils with antitumor activities.

N2

Neutrophils with pro-tumor activities.

NAD+

The oxidized form of nicotinamide adenine dinucleotide, a cofactor involved in redox reactions, transporting electrons from one substrate to another.

NADH

The reduced form of NAD+, a cofactor involved in redox reactions.

NADP+

A coenzyme called nicotinamide adenine dinucleotide phosphate, acting as a cofactor in anabolic metabolism.

NETs

Neutrophil extracellular traps are a defense mechanism, where neutrophils release chromatin to form an extracellular fibril matrix, which traps pathogens.

P2 receptors (P2Y1, P2Y2, P2Y6, P2X1, P2X7)

Receptors that are activated by purines (e.g. ATP, ADP) or pyrimidines (e.g. UTP, UDP).

PNX-1

Pannexin-1 is a large transmembrane channel in the plasmatic membrane, allowing the passage of ions and small molecules, such as ATP.

TLR4

Toll-like receptor 4 is a cell surface receptor activated by LPS derived from Gram-negative bacteria or by endogenous ligands such as HMGB1, which elicit potent innate immune responses in several cells such as macrophages, dendritic cells, and neutrophils.

UDP-glucose

Uridine diphosphate-glucose is a nucleotide sugar involved in glycosyl-transferase reactions that activates one of the P2 purinergic receptors.

VCAM-1

Vascular cell adhesion molecule-1 is a cell adhesion molecule expressed by the vascular endothelium.

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Rubenich, D.S., de Souza, P.O., Omizzollo, N. et al. Neutrophils: fast and furious—the nucleotide pathway. Purinergic Signalling 17, 371–383 (2021). https://doi.org/10.1007/s11302-021-09786-7

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