Project Summary Saliva is essential for maintaining oral health and it has been estimated that more than 5 million people in the US suffers from salivary gland dysfunctions. Primary Sjögren's syndrome (pSS) is an autoimmune disease with unknown etiology and multiple factors have been suggested to play a role in the pathogenesis of pSS. Importantly, infiltrating immune cells (especially Th17 cells), autoantibodies producing B cells, and dendritic cells are shown to be highly present in salivary glands of pSS patients; however, the mechanism as why these immune cells are present in salivary tissues is not known. Although Ca2+ is shown to play a central role in regulating saliva secretion as well as in immune cell activation, information regarding the mechanism that modulate Ca2+ channel activity in pSS is not well understood. Endogenous metabolite, such as lactate was previously considered as a waste product of cellular metabolism, but recently it has been shown that these metabolites effectively modulate the immune response. L-lactate inhibit T cell motility thereby preventing the movement of T cells, back from the inflamed tissues and increase in lactate levels are observed in the salivary glands of pSS mouse models and in pSS patients. Importantly, increase in lactate levels were critical in inhibiting STIM1 migration thereby preventing Ca2+ entry in salivary gland cells that lead to a decrease in ER Ca2+ levels and induced ER stress. Lactate-mediated induction of ER stress releases alarmins that is essential for T/B cell activation and their migration into salivary tissues. Finally, lactate-mediated loss of Orai1 activity resulted in the overproduction of IFN and IL-17 cytokines from CD4+ T cells and inhibited mitochondrial function that was important for metabolic reprograming needed for T cell switching. The objective of this grant is to elucidate the mechanism(s) thereby endogenous metabolites, such as lactate modulates Ca2+ signaling and leads to salivary gland dysfunction. This application is based on the hypothesis that lactate induces autoimmunity by inhibiting Ca2+ entry channels which results in decreased saliva secretion and suppression of the oxidative phosphorylation. The results of our studies are expected to provide new insights into the role of endogenous metabolites in regulating Ca2+ channels and the molecular mechanism involved in salivary gland dysfunction as well as establish ways to restore functional salivary glands. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions.