TY - JOUR TI - Evaluation of the role of cortisol in modulating seasonal changes in immunity DO - https://doi.org/doi:10.7282/T3RR22C1 PY - 2017 AB - Inflammatory diseases such as asthma, rheumatoid arthritis (RA) and systemic vasculitis exhibit seasonality with higher prevalence and aggravated symptoms occurring during the winter months. Though the underlying causes remain to be elucidated, disease seasonality has been associated with circannual changes in antibodies, hormonal levels, acute phase reactants and numerous immunomodulatory components. For instance, RA risk biomarkers such as IL-6R mRNA, sIL-6 receptor and C-reactive proteins vary significantly throughout the year with peak expressions during the winter season. Apart from seasonal variation, the dynamics of functions such as cytokine production and hormone secretion display diurnal fluctuations that are entrained to the external 24-hour light/dark cycle. The light fraction of the light/dark cycle, or photoperiod, varies predictably throughout the year and is a robust environmental cue that synchronizes seasonal variations in neuroendocrine function. It is well established that cortisol, regulated via hypothalamic-pituitary-adrenal (HPA) axis activity and entrained to the external photoperiod, is a potent immunomodulator whose level varies seasonally. A detailed experimental analysis of the role of the HPA axis in regulating seasonal changes in immune function is lacking due to the complex network of biological interactions. In this work, we developed a semi-mechanistic mathematical model to evaluate cortisol’s role in modulating seasonal immunological plasticity. Our results indicate a shift from an anti- to a pro-inflammatory state as the seasons progress from summer through winter with elevated expression of the cortisol-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an inflammatory disease biomarker, predicted for the winter season. Experimentally, the pro-inflammatory phenotype correlated with mitotic asynchrony is mitigated following glucocorticoid-induced cell resynchronization. A cortisol-dependent, time-of-day and seasonal variability in the synchronization of the molecular clock and cell cycle was predicted. These findings have major health implications as the misalignment of internal dynamics with environmental signals has been associated with inflammatory disease progression. The current model provides a framework for exploring the impact of asynchrony between the circadian and cell cycle oscillators, amongst cells in a population, on immune system dynamics. Knowledge of the underlying putative mechanisms governing seasonal and diurnal modifications of immune system dynamics can be applied to design more effective preventative and chronotherapeutic strategies addressing the development and advancement of a pro-inflammatory state. KW - Biomedical Engineering KW - Cortisol KW - Immunity system LA - eng ER -