P2Y2R Deletion Ameliorates Sialadenitis in IL-14α-transgenic Mice

Abstract

Objective

Interleukin-14α-transgenic (IL-14αTG) mice develop an autoimmune exocrinopathy with characteristics similar to Sjögren's syndrome, including sialadenitis and hyposalivation. The P2Y₂ receptor (P2Y₂R) for extracellular ATP and UTP is upregulated during salivary gland inflammation (i.e., sialadenitis) where it regulates numerous inflammatory responses. The present study investigated the role of P2Y₂Rs in autoimmune sialadenitis in the IL-14αTG mouse model of Sjögren's syndrome.

Materials and methods

IL-14αTG mice were bred with P2Y₂R^-/- mice to generate IL-14αTG x P2Y₂R^-/- mice. P2Y₂R expression, lymphocytic focus scores, B and T cell accumulation and lymphotoxin-α expression were evaluated in the submandibular glands along with carbachol-stimulated saliva secretion in IL-14αTG, IL-14αTG x P2Y₂R^-/- and C57BL/6 control mice at 9 and 12 months of age.

Results

Genetic ablation of P2Y₂Rs in IL-14αTG mice significantly reduced B and T lymphocyte infiltration of submandibular glands. However, reduced sialadenitis did not restore saliva secretion in IL-14αTG x P2Y₂R^-/- mice. Decreased sialadenitis in IL-14αTG x P2Y₂R^-/- mice correlated with decreased lymphotoxin-α levels, a critical proinflammatory cytokine associated with autoimmune pathology in IL-14αTG mice.

Conclusions

The results of this study suggest that P2Y₂Rs contribute to the development of salivary gland inflammation in IL-14αTG mice and may also contribute to autoimmune sialadenitis in humans.

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