Psychological stress induces dysfunction in the lacrimal gland through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis

Abstract

Chronic psychosocial stress is increasingly recognized as a key risk factor for dry eye disease, potentially because of its disruption of the circadian transcriptome and lacrimal gland function, which impacts eye health. In this study, we test this hypothesis by using two mouse models (high platform and restraint experiments) of psychological stress and report that both models uniquely alter the circadian transcriptome and signaling pathways of the lacrimal gland. Psychosocial stress significantly affects the normal rhythmic oscillations of extraorbital lacrimal gland (ELG) immune cell trafficking, secretion response, and lipid deposition. Both models significantly reduce the volume of stimulated lacrimal secretions as well as the recruitment of immune cells to the lacrimal gland. Importantly, treatment with beta-adrenergic receptor blockers or glucocorticoid synthesis inhibitors significantly improves these secretory functions and histopathological changes. Collectively, these findings demonstrate the detrimental effects of chronic psychosocial stress on lacrimal gland circadian transcriptome homeostasis and suggest potential clinical applications for patients with both psychological stress and dry eye disease.

1. Introduction

Dry eye disease (DED) is a rising health issue affecting up to one-third of the population, impairing daily activities such as reading and driving and posing economic challenges [1]. Recent evidence links the onset of DED to psychological stressors such as neuroticism, anxiety, and depression [2]. A Korean survey of 16,408 participants revealed DED to be a high-risk factor for suicidal thoughts [3]. Dry eye symptoms are also uniquely associated with increased depression among ocular diseases [4]. In organisms, the lacrimal glands are the primary structures responsible for tear secretion and play a crucial role in preventing the onset of DED. Given the strong associations between various psychological stressors and DED, it is imperative to explore the effects of psychological stress on the physiological homeostasis of the lacrimal gland and the underlying mechanisms involved.

Human beings encounter various daily stressors from societal, personal, occupational, and environmental sources [5]. The body’s physiological responses to these stressors are regulated mainly by circadian and stress systems [6]. The circadian system prepares the body for daily homeostatic stress by upregulating the stress system, primarily through the autonomic and endocrine systems, prior to the daily activity phase [7]. In contrast, unexpected stressors primarily activate the stress system [8]. In general, the stress system functions independently of the circadian system. The circadian master clock, located in the suprachiasmatic nucleus (SCN), remains largely unaffected by stress and consistently maintains the body’s stress state. However, prolonged stress can destabilize the SCN master clock and alter the peripheral clock [9].

Human tear secretion follows a strong circadian rhythm [10], with various rhythmic variables, such as secretion volume [11], osmolarity [12], electrolyte composition [13], pH [14], protein composition [13], and cytokine levels [15]. A previous study indicated that the transcriptome, secretion, and immune cell activity of mouse extraorbital lacrimal glands also exhibit diurnal rhythms [16]. Certain factors, such as dietary challenge [17], jet lag [18], sleep deprivation [19], and hyperglycemic states [16], can significantly alter lacrimal gland rhythmicity. However, the effects of chronic psychological stress on the circadian rhythm, structure, and function of the lacrimal gland remain unclear.

Psychological stress activates a neurobiological response when demands exceed coping ability [20]. In mammals, the sympathetic nervous system (SNS) and the hypothalamic‒pituitary‒adrenal (HPA) axis are crucial for stress management [21]. Chronic stress elevates stress hormones such as norepinephrine and epinephrine, affecting beta-adrenergic receptors on cells. Simultaneously, the HPA axis releases adrenocorticotropic hormone (ACTH), which is stimulated by corticotropin-releasing hormone (CRH), leading to glucocorticoid secretion, which alters metabolism and immune function [22]. These stress response systems are located in interconnected brain regions [23]. The lacrimal gland is influenced by sympathetic innervation and glucocortic