Several empirical observations strongly suggest that salivary function is regulated by the circadian clock. Salivary volume, electrolytes levels, and saliva protein composition all show 24-h cycle fluctuations. The exact effects of circadian disruption on salivary gland (SG) physiology and its potential role in salivary pathologies have not been elucidated. Here, we examined the effects of circadian disruption on SG structure, functional gene and protein expression, and immune status using several circadian knockout (KO) mice models where we targeted the following canonical clock genes: brain and muscle ARNT-like 1 protein () KO, Period2 () KO, Cryptochrome1 () KO, Cryptochrome2 () KO, and Cryptochrome 1 and 2 double KO (). All mice were females of young and old age, and data were compared with wild type (control) mice. Our results showed that circadian dysregulation had limited effects on stimulated salivary secretion and SG structure. Yet, circadian disruption significantly affected the expression of several key salivary markers, including mucins, amylase, and aquaporins, in young and aged SGs with increased amylase and acidic mucin production observed in several KO models. In addition, targeting of clock genes has resulted in subtle alterations of the salivary immune microenvironment with increased lymphocyte infiltration and upregulated levels of proinflammatory cytokines. These immune shifts were more pronounced in aged glands with the most proinflammatory phenotypes observed inandmice. Collectively, our results implicate the circadian clock in the intricate temporal regulation governing SG function. Our data also suggest that circadian dysregulation may predispose to increased tissue stress and inflammation. Exploration of salivary system chronobiology represents a new avenue for salivary disease prevention and treatment. Bmal1Per2Cry1Cry2DKOCry DKOCry Bmal1KO
