Hydrocortisone

Autoimmune diseases are chronic inflammatory conditions characterized by the breakdown of immune tolerance to self-antigens. While genetic and environmental factors play key roles, growing evidence highlights chronic stress as a significant contributor to immune dysregulation through its impact on the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis, primarily via cortisol secretion, serves as the major neuroendocrine mediator of stress responses, influencing both immune regulation and systemic homeostasis. This review synthesizes current literature on HPA axis physiology, the mechanisms of cortisol signaling, and the maladaptive effects of chronic stress. Emphasis is placed on clinical and experimental findings linking HPA dysfunction to immune imbalance and autoimmunity, as well as organ-specific consequences across neuroimmune, endocrine, cardiovascular, gastrointestinal, integumentary, and musculoskeletal systems. Chronic stress leads to impaired HPA axis feedback, glucocorticoid receptor resistance, and paradoxical cortisol dysregulation, fostering a pro-inflammatory state. This dysregulation promotes cytokine imbalance, weakens protective immune mechanisms, and shifts the immune response toward autoimmunity. Evidence from both human and animal studies associates persistent HPA dysfunction with diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. HPA axis dysregulation under chronic stress constitutes a critical mechanistic link between psychological stress and autoimmune disease. Understanding these pathways provides opportunities for therapeutic interventions, including stress management, lifestyle modification, and neuroendocrine-targeted treatments. Future research should focus on multi-omics and longitudinal approaches to clarify the reversibility of HPA alterations and identify resilience factors.

Cortisol, a key hormone in the body’s stress response, plays a complex role in the development and progression of various psychiatric illnesses. Elevated or dysregulated cortisol levels are linked to mood disorders, including anxiety and depression, where both high and low cortisol can impair cognitive function and emotional stability. In children, chronic stress and high cortisol exposure can lead to long-term behavioral problems, affecting memory, decision-making, and emotional regulation, especially when early-life adversity is present. Similarly, in adults, prolonged cortisol dysregulation often contributes to cognitive decline, mood instability, and an increased vulnerability to psychiatric conditions like major depressive disorder and bipolar disorder. Structural changes in stress-sensitive brain regions, such as the hippocampus and amygdala, are common, as chronic cortisol exposure can cause atrophy in these areas, affecting memory, fear responses, and executive function. This relationship underscores the critical role of managing stress and cortisol levels to prevent or alleviate psychiatric symptoms across the lifespan. In this review, the authors highlight the latest findings regarding the cortisol-psychiatric illness relationship and the available treatment options involving this target.

Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.

ImportanceIn randomized trials, early prophylactic hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) with few adverse effects in extremely preterm infants. Large scale implementation data are needed to evaluate clinical effects and safety.ObjectiveTo examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks' postmenstrual age (PMA) in extremely preterm infants in Sweden after guideline implementation and to assess treatment safety.Design, setting, and participantsA national historical cohort study with prospectively collected data from the Swedish Neonatal Quality register from 4 Swedish centers where hydrocortisone prophylaxis was implemented. The study included infants born between 22 and 27 weeks' gestation between 2018 and 2023. Infants were divided into exposed and nonexposed groups according to the intention-to-treat principle.ExposureHydrocortisone, 1 mg/kg/d, for the first 7 days of life, followed by 0.5 mg/kg/d from days 8 through 10.Main outcomes and measuresThe primary outcome was survival without BPD at 36 weeks' PMA. A predefined statistical analysis plan with logistic regression was used to calculate unadjusted and adjusted odds ratios.ResultsAmong 1106 infants (median [IQR] gestational age, 25 weeks, 6 days [24 weeks, 3 days to 27 weeks]; median [IQR] birth weight, 780 [610-964] g), 474 received hydrocortisone prophylaxis and 632 did not. Survival without BPD occurred in 154 of 474 exposed (32.5%) and 185 of 632 nonexposed (29.3%) infants (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27). BPD occurred in 233 exposed (49.2%) and 345 nonexposed (54.6%) infants (adjusted odds ratio, 0.65; 95% CI, 0.49-0.86). Death before 36 weeks' PMA occurred in 87 exposed (18.4%) and 102 nonexposed (16.1%) infants. Late-onset bacterial infection was more common in exposed infants, but not significant after adjustment. No other severe neonatal morbidities differed significantly between the 2 groups.Conclusions and relevanceIn this cohort study of extremely preterm infants, the introduction of prophylactic hydrocortisone was associated with increased survival without BPD, after adjusting for covariates. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments.