Targeting P2 Receptors to Restore Salivary and Lacrimal Gland Function in Sjogren's Syndrome

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Summary Sjögren’s syndrome (SS), an autoimmune exocrinopathy of the salivary and lacrimal glands, affects ~ 4 million Americans, 90% of whom are women. SS is characterized by sialadenitis and dacryoadenitis, decreased saliva (i.e., xerostomia) and tear production (i.e., xerophthalmia) and the presence in blood serum of autoantibodies against Ro/SSA and La/SSB. Xerostomia and xerophthalmia in SS patients can lead to periodontitis, yeast and bacterial infections, digestive disorders and vision deterioration that severely reduce the quality of life for patients. Ultimately, chronic inflammation in SS leads to secondary autoimmune diseases, tissue fibrosis and lymphoma. Therapy for SS is limited to symptom management through external hydration, artificial saliva and tears and muscarinic receptor agonists that induce fluid secretion from residual exocrine acinar cells. Such remedies are universally judged to be inadequate and thus, development of more effective SS treatments is essential. Our research focuses on cell surface P2X7 and P2Y2 receptors for extracellular ATP, the intracellular chemical form of energy that when released from damaged salivary glands initiate inflammatory responses. Our studies show that P2X7R and P2Y2R antagonists enhance saliva secretion and reduce lymphocytic foci in salivary glands of two different mouse models of SS. Antagonism of the P2X7R also reduces lymphocytic accumulation in the lacrimal glands and increases tear secretion. These antagonists have not been used to treat human SS, although P2X7R is upregulated in salivary glands of SS patients compared to non-SS controls. P2X7R activation in salivary glands also induces maturation and release of IL-1β, an SS- related cytokine that upregulates P2Y2R in immune and epithelial cells, suggesting that P2X7R and P2Y2R contribute together to SS development. This project will investigate the ability of P2X7R and/or P2Y2R antagonists to increase saliva and/or tear secretion and reduce sialadenitis and/or dacryoadenitis in mouse models of SS. These findings will be validated by assessing P2X7R and P2Y2R expression in archived human SS and control minor salivary gland biopsies and evaluating effects of P2X7R and/or P2Y2R antagonism in freshly isolated human salivary and lacrimal gland cells. Specific Aim 1 will investigate the hypothesis that P2X7R and P2Y2R play sequential roles in chronic sialadenitis and glandular dysfunction in SS mouse models and can be antagonized to treat SS in vivo. Specific Aim 2 will investigate the hypothesis that P2X7R and P2Y2R activation in lacrimal gland epithelial cells promotes dry eye disease in mouse models of SS. Specific Aim 3 will investigate P2X7R and P2Y2R-mediated proinflammatory responses in human primary salivary and lacrimal gland cells and human SS minor salivary gland biopsies. Successful completion of this proposal will represent a critical step towards realization of the ultimate goal of targeting the P2X7R and/or P2Y2R to treat SS in humans.