Sex differences in the regulation of brain IL-1β in response to chronic stress

Abstract

Elevations in brain interleukin-1 beta (IL-1β) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1β production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: β-AR) IL-1 β production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the "yin-yang" balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1β. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (β-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1β mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1β expression in non-stressed controls but significantly reduced IL-1β in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1β in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1β mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1β in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1β indicating the increase in brain IL-1β following metyrapone treatment was due to increase β-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1β. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1β by the norepinephrineβ-AR pathway, while stress had no effect in the regulation of brain IL-1β in female rats.

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy

“…Further, this study confirmed that sex hormones were correlated with cortisol levels, thereby linking sex hormones with stressinduced cortisol responses in men and women. In support of these clinical findings, sex differences in corticosterone regulation of repeated stress-induced inflammation in rodents is also well recognized (Barnard et al, 2019). Taken together these clinical and preclinical studies provide evidence whereby, through modulating release of the anti-inflammatory hormone cortisol in the context of social stress or through direct regulation of microglia via estrogen receptors, sex hormones may be promoting exaggerated inflammatory responses in females and anti-inflammatory responses in males.…”

Serum Vitamin D Concentrations Are Associated With Depressive Symptoms in Men: The Sixth Korea National Health and Nutrition Examination Survey 2014

“…Third, the effect of chronic stress in depression could provide more information on the role of vitamin D, as it is known as a relevant risk factor of cognitive/affective depressive symptoms (35). Chronic stress induced dendritic atrophy in hippocampal pyramidal neurons (36), and affected the regulation of Interleukin 1 beta (IL-1ß) (37), only in male rats. Additionally, social isolation stress tests induced anhedonia-like behavior only in male rats, and reductions in synaptic proteins and spine density after social isolation were reversed by ketamine only in male rats (38).…”

Neuroendocrine Regulation of Brain Cytokines After Psychological Stress

“…However, there are reasons to believe that after stress exposure, IL-1 β is primarily produced by microglia. This is because isoproterenol (a β -AR agonist) induces IL-1 β mRNA in cultured microglia but not in astrocytes [69], administration of minocycline prevents stress-induced increases in brain IL-1 β [40, 70], and the induction of IL-1 β after stress or metyrapone treatment (a corticosterone synthesis inhibitor) is observed in CD11b+ cells [45, 71].…”