Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction
ObjectivesCD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells’ “purinergic halo” in maintaini...
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Frontiers Media S.A.
2018-06-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01322/full |
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author | Jason S. Knight Levi F. Mazza Srilakshmi Yalavarthi Gautam Sule Ramadan A. Ali Jeffrey B. Hodgin Yogendra Kanthi Yogendra Kanthi David J. Pinsky David J. Pinsky |
author_facet | Jason S. Knight Levi F. Mazza Srilakshmi Yalavarthi Gautam Sule Ramadan A. Ali Jeffrey B. Hodgin Yogendra Kanthi Yogendra Kanthi David J. Pinsky David J. Pinsky |
author_sort | Jason S. Knight |
collection | DOAJ |
description | ObjectivesCD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells’ “purinergic halo” in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus.MethodsLupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39−/−, and CD73−/−. After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized.ResultsAs compared with WT mice, CD39−/− mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39−/− and CD73−/− mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73−/− mice, while deficiency of either ectonucleotidase led to expansion of TH17 cells. CD39−/− and CD73−/− mice demonstrated exaggerated neutrophil extracellular trap release, while CD73−/− mice additionally had higher levels of plasma cell-free DNA.ConclusionThese data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus. |
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publishDate | 2018-06-01 |
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series | Frontiers in Immunology |
spelling | doaj.art-973f655119194c3bbe655ed5cc22bac52022-12-22T03:43:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-06-01910.3389/fimmu.2018.01322344264Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular DysfunctionJason S. Knight0Levi F. Mazza1Srilakshmi Yalavarthi2Gautam Sule3Ramadan A. Ali4Jeffrey B. Hodgin5Yogendra Kanthi6Yogendra Kanthi7David J. Pinsky8David J. Pinsky9Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDepartment of Pathology, University of Michigan, Ann Arbor, MI, United StatesDivision of Cardiology, Ann Arbor Veterans Administration Healthcare System, Ann Arbor, MI, United StatesDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United StatesDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United StatesObjectivesCD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells’ “purinergic halo” in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus.MethodsLupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39−/−, and CD73−/−. After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized.ResultsAs compared with WT mice, CD39−/− mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39−/− and CD73−/− mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73−/− mice, while deficiency of either ectonucleotidase led to expansion of TH17 cells. CD39−/− and CD73−/− mice demonstrated exaggerated neutrophil extracellular trap release, while CD73−/− mice additionally had higher levels of plasma cell-free DNA.ConclusionThese data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus.https://www.frontiersin.org/article/10.3389/fimmu.2018.01322/fullsystemic lupus erythematosusectonucleotidasesCD73CD39TH17 cellsendothelial dysfunction |
spellingShingle | Jason S. Knight Levi F. Mazza Srilakshmi Yalavarthi Gautam Sule Ramadan A. Ali Jeffrey B. Hodgin Yogendra Kanthi Yogendra Kanthi David J. Pinsky David J. Pinsky Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction Frontiers in Immunology systemic lupus erythematosus ectonucleotidases CD73 CD39 TH17 cells endothelial dysfunction |
title | Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction |
title_full | Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction |
title_fullStr | Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction |
title_full_unstemmed | Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction |
title_short | Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction |
title_sort | ectonucleotidase mediated suppression of lupus autoimmunity and vascular dysfunction |
topic | systemic lupus erythematosus ectonucleotidases CD73 CD39 TH17 cells endothelial dysfunction |
url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01322/full |
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