# Purinergic modulation of the autoimmune vascular phenotype

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $567,640

## Abstract

ABSTRACT
Dead and dying cells release purine nucleotides, which engage purinergic receptors on the surfaces of
leukocytes, platelets, and vascular cells to trigger inflammation, coagulation, and vasoconstriction. To counter
these mediators of vascular disequilibrium, leukocytes and endothelial cells express surface ectonucleotidases
(CD39 and CD73), which catalyze the step-wise phosphohydrolysis of ATP into adenosine—thereby creating
an anti-inflammatory, antithrombotic “halo” around the cell. In patients with systemic lupus erythematosus
(commonly referred to as “lupus”), stroke and venous thrombosis are relentlessly driven by oxidative stress
and prothrombotic autoantibodies. Furthermore, our laboratory recently discovered that neutrophil extracellular
traps (NETs, tangles of chromatin expelled by “NETosis”) trigger endothelial damage and in situ thrombosis in
lupus. Our preliminary data now reveal that, in lupus, CD73 counteracts neutrophil infiltration, NETosis,
dysfunction of the arterial endothelium, and venous thrombosis. The hypothesis driving this work is that CD73
and its downstream pathways serve as an endogenous (and potentially amplifiable) counterpoint to thrombo-
inflammatory events in lupus.
The Aims of this project are to: (1) Elucidate cell- and receptor-specific mechanisms by which CD73 protects
against lupus-mediated dysfunction of the arterial endothelium. In addition to two traditional models of murine
lupus, we will use a novel approach whereby the administration of human lupus autoantibodies into mice
rapidly triggers endothelial dysfunction. Endpoints will determine the mechanism(s) by which CD73 and
adenosine receptors (A2A, A2B, A3) thwart arterial inflammation and endothelial dysfunction in lupus-prone mice,
and will define the extent to which lineage-specific expression of CD73 (neutrophils vs. endothelium) guards
against these phenotypes. Endpoints will also globally assess the deranged autoimmune/inflammatory milieu
of lupus. (2) Ascertain how CD73 and downstream purinergic signaling modulate lupus-mediated venous
thrombosis. Experiments will again leverage traditional models of murine lupus, as well as a novel model
whereby human lupus autoantibodies markedly potentiate venous thrombosis in mice. We will determine the
extent to which lineage-specific expression of CD73 protects against venous thrombosis, and will elucidate
mechanism(s) by which CD73 and adenosine receptors mitigate autoantibody-mediated NETosis.
Overall, these studies should yield new insight into how a pathway that functions as an endogenous guardian
against inflammation may be exploited to counteract the relentless thrombo-inflammatory course of lupus.

## Key facts

- **NIH application ID:** 10077331
- **Project number:** 5R01HL134846-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jason Knight
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $567,640
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077331

## Citation

> US National Institutes of Health, RePORTER application 10077331, Purinergic modulation of the autoimmune vascular phenotype (5R01HL134846-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10077331. Licensed CC0.

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