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A1 and A2A adenosine receptors play a protective role to reduce prevalence of autoimmunity following tissue damage
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  • Reut Riff,
  • Oshri Naamani,
  • julia mazar,
  • Yosef Haviv,
  • Cidio Chaimovitz,
  • Amos Douvdevani
Reut Riff
Ben-Gurion University of the Negev

Corresponding Author:reutriff@gmail.com

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Oshri Naamani
Ben-Gurion University of the Negev
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julia mazar
Soroka Medical Center
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Yosef Haviv
Soroka Medical Center
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Cidio Chaimovitz
Soroka Medical Center
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Amos Douvdevani
Ben-Gurion University of the Negev
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Abstract

Tissue damage associated with trauma might release a sufficient autoantigen substrate to break immune tolerance. In a previous study, we showed that the leukopenia observed following severe inflammation is related to adenosine A1-receptor (A1R) desensitization and A2AR upregulation. We hypothesized that, under destructive pathological conditions this mechanism is beneficial in reducing prevalence of autoimmunity. In this study, we aim to evaluate the protective role of A1R and A2AR in prevention of autoimmune diseases. We used two murine models of autoimmune diseases: type 1 diabetes (T1D) induced by low-dose streptozotocin and pristane-induced lupus (PIL) and on neutrophils we studied NETosis regulation by adenosine. In both the T1D and PIL models, A1R-KO mice were predisposed to the development of autoimmunity. In the PIL model, in WT mice, parallel to the decline of A1R mRNA levels, lymphocytes number dropped (-85%) 6h after pristane injection. WT mice remained without any sign of disease at 36 weeks. In contrast, following pristane 43% of A1R-KO mice suffered from lupus-like disease. Compared to A1R-KO, in WT mice at 10 days A2AR mRNA levels were significantly higher. Similar to PIL, in T1D model the presence of A1R and A2AR was protective. In addition, we found that A1R increases and A2AR suppresses NETosis. We suggest that adenosine-dependent immune suppression and reduction in neutrophil extracellular traps (NETs) limits the reactive T-cells and development of anti-double strand DNA (dsDNA) antibodies that promote autoimmunity.
23 Sep 2020Submitted to Clinical & Experimental Immunology
24 Sep 2020Submission Checks Completed
24 Sep 2020Assigned to Editor
24 Sep 2020Reviewer(s) Assigned
14 Oct 2020Review(s) Completed, Editorial Evaluation Pending
14 Oct 2020Editorial Decision: Revise Major
19 Mar 20211st Revision Received
22 Mar 2021Reviewer(s) Assigned
23 Mar 2021Review(s) Completed, Editorial Evaluation Pending
24 Mar 2021Editorial Decision: Revise Major
24 Mar 20212nd Revision Received
25 Mar 2021Reviewer(s) Assigned
27 Mar 2021Review(s) Completed, Editorial Evaluation Pending
27 Mar 2021Editorial Decision: Accept
Sep 2021Published in Clinical & Experimental Immunology volume 205 issue 3 on pages 278-287. 10.1111/cei.13607