Circadian clock-dependent increase in salivary IgA secretion modulated by sympathetic receptor activation in mice

Abstract

The salivary gland is rhythmically controlled by sympathetic nerve activation from the suprachiasmatic nucleus (SCN), which functions as the main oscillator of circadian rhythms. In humans, salivary IgA concentrations reflect circadian rhythmicity, which peak during sleep. However, the mechanisms controlling this rhythmicity are not well understood. Therefore, we examined whether the timing of parasympathetic (pilocarpine) or sympathetic (norepinephrine; NE) activation affects IgA secretion in the saliva. The concentrations of saliva IgA modulated by pilocarpine activation or by a combination of pilocarpine and NE activation were the highest in the middle of the light period, independent of saliva flow rate. The circadian rhythm of IgA secretion was weakened by an SCN lesion and Clock gene mutation, suggesting the importance of the SCN and Clock gene on this rhythm. Adrenoceptor antagonists blocked both NE-and pilocarpine-induced basal secretion of IgA. Dimeric IgA binds to the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The circadian rhythm of Pigr abundance peaked during the light period, suggesting pIgR expression upon rhythmic secretion of IgA. We speculate that activation of sympathetic nerves during sleep may protect from bacterial access to the epithelial surface through enhanced secretion of IgA.Mammals possess circadian clock systems that control various physiological phenomena such as body temperature, sleep-wake cycles, and liver metabolism 1, 2 . Circadian clock systems are organized by a central clock called the suprachiasmatic nuclei (SCN) 3 , and by peripheral clocks located in many peripheral organs 4,5 . In addition to this system, biological functions of metabolism and the immune system are also known to affect circadian rhythms 6,7 .IgA is a type of antibody that works mainly in the mucosal immune system. It is abundant in the mucus of saliva and the small intestine 8 . Since plasma cells produce IgA in the salivary glands, there is a large amount of IgA in saliva. Therefore, IgA plays an important role as the first line of defense in oral immunity 9 . Monomers of IgA form dimeric IgA (dIgA) through the J chain. This dIgA binds the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The IgA-pIgR complex is transported to the lumen from the basolateral surface. Proteolytic cleavage occurs at the apical surface, and a fragment of pIgR becomes a secretory component (SC) that binds dIgA. In this way, secretory IgA (sIgA) combines with other SCs, and free SCs are released. As a result, sIgA binds to luminal bacteria and prevents them from accessing the epithelial surface 9 . Therefore, a reduction in salivary IgA levels allows bacterial access to the epithelial surface and leads to various diseases such as upper respiratory tract infections (URTI) and periodontal disease 10 . A few studies demonstrated that salivary IgA concentrations display diurnal variat...

Salivary Immunoglobulin A Secretion and Polymeric Ig Receptor Expression in the Submandibular Glands Are Enhanced in Heat-Acclimated Rats

“…Salivary IgA secretion is rhythmically controlled by sympathetic nerve activation by the suprachiasmatic nucleus, which functions as the main oscillator of circadian rhythms [40,41]. The circadian rhythms of pIgR expression and IgA secretion in mice peaked during the light period, and the circadian control of salivary IgA secretion vanished in clock KO mice [41].…”

Crosstalk Among Circadian Rhythm, Obesity and Allergy

“…Indeed, studies in mice revealed that glucose tolerance testing at the beginning or middle of the active period produced lower blood glucose levels than the idle period [18]. Other studies showed that food antigen exposure in the late inactive period caused more severe food allergy symptoms than in the late active period [19] and that salivary IgA secretion rhythm was abolished by SCN lesion [20]. Therefore, keeping an accurate circadian clock system is vital for maintaining normal physiological functions.…”

Daytime Exposure to Blue-Enriched Light Counters the Effects of Sleep Restriction on Cortisol, Testosterone, Alpha-Amylase and Executive Processes

“…Alpha-amylase is both an antimicrobial peptide with a key role in mucosal immunity and a surrogate of catecholamine changes in the blood, considered as a reliable stress marker of SNS activity (Nater and Rohleder, 2009). Two additional salivary markers reported to be sensitive to sleep deprivation and stress system activities, immunoglobulin A (IgA, which serves as a first line of immune defense against microbial infection) and testosterone (a gonadal steroid hormone involved in the development and maintenance of the male reproductive system, in muscle protein synthesis and vigor) were here assessed (Leproult and Van Cauter, 2011;Toufexis et al, 2014;Wada et al, 2017).…”