Rationale: Mechanical ventilation (MV) is life-saving but may evoke ventilator-induced lung injury (VILI). Objectives: To explore how the circadian clock modulates severity of murine VILI via the core clock component BMAL1 (basic helix-loop-helix ARNT like 1) in myeloid cells. Methods: Myeloid cell BMAL1-deficient (LysM (lysozyme 2 promoter/enhancer driving cre recombinase expression)^Bmal1-/-) or wild-type control (LysM^Bmal1+/+) mice were subjected to 4 hours MV (34 ml/kg body weight) to induce lung injury. Ventilation was initiated at dawn or dusk or in complete darkness (circadian time [CT] 0 or CT12) to determine diurnal and circadian effects. Lung injury was quantified by lung function, pulmonary permeability, blood gas analysis, neutrophil recruitment, inflammatory markers, and histology. Neutrophil activation and oxidative burst were analyzed ex vivo. Measurements and Main Results: In diurnal experiments, mice ventilated at dawn exhibited higher permeability and neutrophil recruitment compared with dusk. Experiments at CT showed deterioration of pulmonary function, worsening of oxygenation, and increased mortality at CT0 compared with CT12. Wild-type neutrophils isolated at dawn showed higher activation and reactive oxygen species production compared with dusk, whereas these day-night differences were dampened in LysM^Bmal1-/- neutrophils. In LysM^Bmal1-/- mice, circadian variations in VILI severity were dampened and VILI-induced mortality at CT0 was reduced compared with LysM^Bmal1+/+ mice. Conclusions: Inflammatory response and lung barrier dysfunction upon MV exhibit diurnal variations, regulated by the circadian clock. LysM^Bmal1-/- mice are less susceptible to ventilation-induced pathology and lack circadian variation of severity compared with LysM^Bmal1+/+ mice. Our data suggest that the internal clock in myeloid cells is an important modulator of VILI.

Patients admitted to the intensive care unit (ICU) are in need of continuous organ replacement strategies and specialized care, for example because of neurological dysfunction, cardio-pulmonary instability, liver or kidney failure, trauma, hemorrhagic or septic shock or even preterm birth. The 24-h nursing and care interventions provided to critically ill patients significantly limit resting and/or recovery phases. Consecutively, the patient's endogenous circadian rhythms are misaligned and disrupted, which in turn may interfere with their critical condition. A more thorough understanding of the complex interactions of circadian effectors and tissue-specific molecular clocks could therefore serve as potential means for enhancing personalized treatment in critically ill patients, conceivably restoring their circadian network and thus accelerating their physical and neurocognitive recovery. This review addresses the overarching issue of how circadian rhythms are affected and disturbed in critically ill newborns and adults in the ICU, and whether the conflicting external or environmental cues in the ICU environment further promote disruption and thus severity of illness. We direct special attention to the influence of cell-type specific molecular clocks on with severity of organ dysfunctions such as severity of brain dysfunction, pneumonia- or ventilator-associated lung inflammation, cardiovascular instability, liver and kidney failure, trauma, and septic shock. Finally, we address the potential of circadian rhythm stabilization to enhance and accelerate clinical recovery.

Shift work is associated with systemic chronic inflammation, impaired host and tumor defense and dysregulated immune responses to harmless antigens such as allergens or auto-antigens. Thus, shift workers are at higher risk to develop a systemic autoimmune disease and circadian disruption with sleep impairment seem to be the key underlying mechanisms. Presumably, disturbances of the sleep-wake cycle also drive skin-specific autoimmune diseases, but epidemiological and experimental evidence so far is scarce. This review summarizes the effects of shift work, circadian misalignment, poor sleep, and the effect of potential hormonal mediators such as stress mediators or melatonin on skin barrier functions and on innate and adaptive skin immunity. Human studies as well as animal models were considered. We will also address advantages and potential pitfalls in animal models of shift work, and possible confounders that could drive skin autoimmune diseases in shift workers such as adverse lifestyle habits and psychosocial influences. Finally, we will outline feasible countermeasures that may reduce the risk of systemic and skin autoimmunity in shift workers, as well as treatment options and highlight outstanding questions that should be addressed in future studies.

Over the past four decades, research on 24-h rhythms has yielded numerous remarkable findings, revealing their genetic, molecular, and physiological significance for immunity and various diseases. Thus, circadian rhythms are of fundamental importance to mammals, as their disruption and misalignment have been associated with many diseases and the abnormal functioning of many physiological processes. In this article, we provide a brief overview of the molecular regulation of 24-h rhythms, their importance for immunity, the deleterious effects of misalignment, the link between such pathological rhythms and rheumatoid arthritis (RA), and the potential exploitation of chronobiological rhythms for the chronotherapy of inflammatory autoimmune diseases, using RA as an example.

Objective: The global rise of autoimmune diseases presents a significant medical challenge, with inadequate treatment options, high morbidity risks, and escalating healthcare costs. While the underlying mechanisms of autoimmune disease development are not fully understood, both genetic predispositions and lifestyle factors, particularly sleep, play critical roles. Insomnia and circadian rhythm sleep disorders not only impair sleep but also disrupt multi-organ interactions by dysregulating sympathetic nervous system activity, altering immune responses, and influencing neuroendocrine function. These disruptions can contribute to immune system dysregulation, increasing the risk of autoimmune disease development.

Methods: To assess the impact of impaired sleep on the risk of developing autoimmune diseases, a global population-based retrospective cohort study was conducted using electronic health records from the TriNetX US Global Collaborative Network, including 351,366 subjects in each propensity score matched group. Twenty autoimmune diseases were examined, and propensity score matching was employed to reduce bias. Three sensitivity analyses were conducted to test the robustness of the results.

Results: The study identified significantly increased risks for several autoimmune diseases associated with impaired sleep, likely mediated by dysregulated neuroimmune and autonomic interactions. Specifically, cutaneous lupus erythematosus [hazard ratio (HR) = 2.119; confidence interval (CI) 1.674-2.682; p < 0.0001], rheumatoid arthritis (HR = 1.404; CI 1.313-1.501; p < 0.0001), Sjögren syndrome (HR = 1.84; CI 1.64-2.066; p < 0.0001), and autoimmune thyroiditis (HR = 1.348; CI 1.246-1.458; p < 0.0001) showed significantly increased risks. No diseases demonstrated reduced risks, and 4 out of 20 tested diseases did not show significant HR increases in any analysis.

Conclusion: This study highlights the integral role of sleep in maintaining immune homeostasis through multi-organ interactions involving the autonomic nervous system, immune signalling pathways, and endocrine regulation. Disruptions in these systems due to chronic sleep impairment may predispose individuals to autoimmune diseases by altering inflammatory responses and immune tolerance. These findings underscore the necessity of recognizing and treating sleep disorders not only for general wellbeing but also as a potential strategy to mitigate the long-term risk of autoimmune disease development.

Keywords: TriNetX; autoimmune diseases; autoimmunity; insomnia; retrospective cohort study; sleep.

Adoptive cell therapies (ACTs), such as chimeric antigen receptor (CAR)-T cell therapy, have revolutionized cancer treatment, especially for hematological cancers. However, patient responses vary considerably. Emerging research reveals a striking influence of time of day (ToD) on ACT efficacy. Administering ACT during the early behavioral active phase enhances tumor control and reduces toxicity in preclinical models, an effect linked to the circadian clock. Latest clinical data also point to ToD effects in the cancer setting. In this opinion article we explore current insights and discuss the emerging underlying mechanisms. We propose that integrating ToD into clinical practice could represent a powerful yet easily implementable therapeutic regimen to improve efficacy and safety of ACT.