The significant role that an irregular body clock plays in driving inflammation in the body’s immune cells

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New research from RCSI has demonstrated the significant role that an irregular body clock plays in driving inflammation in the body’s immune cells, with implications for the most serious and prevalent diseases in humans.

Published in Frontiers in Immunology, the research was led by the School of Pharmacy and Biomolecular Sciences at RCSI University of Medicine and Health Sciences.

The circadian body clock generates 24-hour rhythms that keep humans healthy and in time with the day/night cycle. This includes regulating the rhythm of the body’s own (innate) immune cells called macrophages.

When these cell rhythms are disrupted (due to things like erratic eating/sleeping patterns or shift work), the cells produce molecules which drive inflammation. This can lead to chronic inflammatory diseases such as heart disease, obesity, arthritis, diabetes and cancer, and also impact our ability to fight infection.

In this study, the researchers looked at these key immune cells called macrophages with and without a body clock under laboratory conditions. They were interested to understand if macrophages without a body clock might use or ‘metabolise’ fuel differently, and if that might be the reason these cells produce more inflammatory products.

The researchers found that macrophages without a body clock took up far more glucose and broke it down more quickly than normal cells. They also found that, in the mitochondria (the cells energy powerhouse), the pathways by which glucose was further broken down to produce energy were very different in macrophages without a clock. This led to the production of reactive oxygen species (ROS) which further fuelled inflammation.

Dr. George Timmons, lead author on the study, said: “Our results add to the growing body of work showing why disruption of our body clock leads to inflammatory and infectious disease, and one of the aspects is fuel usage at the level of key immune cells such as macrophages.”

Dr. Annie Curtis, senior lecturer at RCSI School of Pharmacy and Biomolecular Sciences and senior author on the paper, added: “This study also shows that anything which negatively impacts on our body clocks, such as insufficient sleep and not enough daylight, can impact on the ability of our immune system to work effectively.”


The 2017 Nobel Prize for Physiology or Medicine has been awarded to three of the principal scientists who contributed to the discovery of the network of genes and proteins regulating the circadian rhythms based on the light/dark 24 h cycle (“The 2017 Nobel Prize in Physiology or Medicine—Press Release”) [1–3].

Circadian clocks are present in unicellular organisms, in plants, insects and vertebrates [4]. The first gene encoding a critical component of a circadian clock (Period) was discovered in Drosophila by Konopka and Benzer in 1971 [5], showing that circadian clocks are genetically encoded.

In mammals, circadian clocks are found in nearly all cells and tissues. They regulate and control physiological processes at the cellular, organ and organismal level, integrating signals received from outside and generated by the normal metabolism. The purpose of different levels of control is to adjust for possible local perturbations, while maintaining a circadian rhythm able to optimize energy allocation for the most likely scenario (which differs during activity and rest periods).

For example, the liver clock should be synchronized to rhythms in food intake, but it should also respond to changes in energy demands or variations in oxygen supply. The organization of the mammalian multi-clock system allows for better adaptation to changing environments. This may represent a compromise between flexible adaptation to extremely unpredictable events and circadian stability, which can distinguish also the changes of light–dark hours (and temperature, humidity etc.) with the different seasons [4, 6].

Time keeping signals (“zeitgeber”) in natural conditions are tied to the day-night cycle imposed by the 24 h rotation cycle of the Earth. Light, this very potent zeitgeber, regulates the 24 h sleep–wake rhythm. Sleep precludes both food intake and locomotor activity. Thus, the sleep–wake rhythm governed by sunlight indirectly drives food intake and body temperature cycles. However light and food can be uncoupled (e.g. in the case of jetlag or when food intake is restricted to the natural sleeping phase as in shift work), causing misalignment of these clocks with the daily light–dark cycle of our environment [7, 8].

The field was stimulated by the finding of an intrinsically photosensitive small subgroup of retinal ganglion cells which regulate the circadian rhythms on the light–dark cycle [9, 10] and project to the suprachiasmatic nuclei (SCN) [11], the non-visual brain centers where the mammalian master biological clock is located; this has prompted the search for the molecular clock(s) driving this essential component of all living organisms. A handful of genes and proteins accounting for this complex regulatory central network has been identified.

Biological clocks
The mammalian core molecular clock consists of two feedback loops [12] connected by a central pair of transcription factors which regulate reciprocally to induce the rhythm of gene expression. The mammalian circadian clock fundamentally depends on two master genes (CLOCK and BMAL1) to drive gene expression and regulate biological functions [6]. CLOCK:BMAL1 heterodimers promote rhythmic chromatin opening and this mediates the binding of other transcription factors adjacent to CLOCK:BMAL1 [13].

Among their targets there is a group of regulatory proteins [PERIOD (PER1, 2 and 3), CRYPTOCHROME (CRY1 and 2), REV-ERB (REV-ERBa and b) and RAR-Related Orphan Receptor (RORa, b and c)]; REV-ERBs and RORs regulate BMAL1 transcription, whereas PER and CRY dimerize to inhibit the BMAL1–CLOCK dimer. PER, the protein encoded by period [14, 15] accumulates during the night and is degraded during the day, while other components allow nuclear translocation of PER [16, 17]. Both sleep–wake cycles and many 24-h rhythms persist in the absence of environmental cues and are controlled by internal molecular clocks [18].

Several loops dictate the production of these proteins, including steps of acetylation and phosphorylation, as well as secondary clock-regulated genes which can also feed back on central clock genes [6, 19]. In fact many different organs and tissues express functional molecular clock circuits [20].

None of the mammalian clock components is directly photoreceptive; instead, light signals from the retina are transmitted neuronally to transcription factors that regulate period expression. Transcriptional feedback loops are central to the generation and maintenance of circadian rhythms [21, 22]. Clocks in peripheral tissues use essentially the same molecular components as in the SCN; clocks have been detected in different hematopoietic cell lineages, including macrophages and lymphocytes [22, 23].

The origin of circadian rhythms

In humans, circadian rhythms of 24 h must be synchronized to coincide with the daily rotational cycle of the earth. The alignment of this autonomous circadian rhythm to an external rhythm is defined as entrainment. The light patterns represent the principal environmental stimulus for the rest/activity and sleep/wake cycles [24]. It is also indirectly responsible for timing of food intake, another powerful entrainer of rhythm [24, 25].

Circadian photoentrainment is the process by which the internal clock in the deep brain becomes synchronized with the daily external cycle of solar light and dark [4, 9, 26]. The clocks in most mammalian cells are not directly photoreceptive, unlike those of most other organisms, but instead are entrained indirectly to the environmental light–dark cycle via photoreception in the retina, the retino-hypothalamic tract, and a central pacemaker tissue in the suprachiasmatic nucleus (SCN) of the hypothalamus [19].

This process is initiated by a type of retinal ganglion cells that send axonal projections to the SCN, the region of the circadian pacemaker (Fig. 1). In contrast to retinal cells mediating vision, these cells are intrinsically sensitive to light, independent of synaptic input from rod and cone photoreceptors [27]. Photoentrainment of the master pacemaker needs signaling from retinal ganglion cells containing the photopigment melanopsin and intrinsically photosensitive [10].

The cryptochrome/photolyase family of photoreceptors mediates adaptive responses to ultraviolet and blue light exposure in all life forms [28]. The SCN subsequently synchronizes peripheral clocks via mediators including hormones and neuronal signals, primarily using the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system [6].

The principal hormones i.e. glucocorticoids and catecholamines (epinephrine and norepinephrine), are released by the adrenal gland via the HPA axis [29], but norepinephrine is also derived from sympathetic nerve endings. The HPA is controlled by the SCN which projects to the paraventricular nucleus of the hypothalamus, and this in turn induces the release of adrenocorticotropic hormone by the pituitary, thus regulating the adrenal gland [20, 30].

Catecholamines act via adrenergic receptors, which have many effects on immune cells, as well as increasing the humoral immune responses [24].

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Fig. 1
Schematic representation of the master clock regulation of the immune system. Entrainment of the suprachiasmatic nuclei (SCN) is mediated by the input from intrinsically photosensitive retinal ganglion cells activated by light (from the sun and artificial lights from screens and indoor illumination). SCN controls directly the hypothalamus and the hypothalamus–pituitary–adrenal gland (HPA) axis, the autonomous nervous system and the pineal gland. Hormones and neurotransmitters (in boxes) from these clock-regulated structures modulate the activation and functions of different cell types of both the innate and adaptive immune system. Cytokines and chemokines produced by immune cells feed back on the SCN (dotted line). Through transcriptional mechanisms the SCN indirectly regulates also the synchronization of secondary clocks in peripheral tissues and other circadian cycles (wake/sleep, fast/feeding, etc.). NE norepinephrine

The integrated circadian system
The central biological CLOCK system, influenced by light/dark changes, ‘creates’ the internal circadian rhythms, and the organism ‘feels’ these changes to put in frame physical activities, including energy metabolism, sleep, and immune function.

A recent review [31] listed the following pathological conditions showing diurnal or 24 h patterning, by the organ/tissue/system affected, skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer, biliary colic, hepatic variceal hemorrhage, and proctalgia; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson’s and Alzheimer’s disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathy, burning mouth and temporomandibular syndromes, fibromyalgia, sciatalgia, and migraine, headache); renal: colic and nocturnal enuresis and polyuria; ocular: conjunctival redness, keratoconjunctivitis sicca, intraocular pressure, anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, suicide, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritides, gout, Sjogren’s syndrome, and systemic lupus erythematosus. Some are directly linked to disruption of circadian rhythms, others result in disturbed sleep with loss of rhythmicity; the peripheral clocks in different tissues become out of phase with the central regulator and other physiologic functions, and this in turn aggravates the symptoms and alters the clinical picture.

Relevance to immunological functions
A wide range of immune parameters, such as the number of peripheral blood mononuclear cells as well as the level of cytokines, undergo daily fluctuations [32]. Total numbers of hematopoietic stem cells and most mature leukocytes peak in the circulation during the resting phase (during the night for humans) and decrease during the day [24]. Most immune cells express circadian clock genes and present a wide array of genes expressed with a 24-h rhythm.

In addition to their functions in the cellular clock, circadian oscillators also participate in the development and specification of immune cell lineages. This has profound impacts on cellular functions, including a daily rhythm in the synthesis and release of cytokines, chemokines and cytolytic factors, the daily gating of the response occurring through pattern recognition receptors, circadian rhythms of cellular functions such as phagocytosis, migration to inflamed or infected tissue, cytolytic activity, and proliferative response to antigens [33].

A pioneering contribution to this area was made by Halberg [34] who discovered a diurnal susceptibility pattern in mice challenged with bacterial endotoxin. The migration of hematopoietic cells to tissues preferentially occurs during the daytime, directed by the circadian expression of cell adhesion molecules and chemokines. During the active phase it is more likely to encounter and detect pathogens and leukocyte trafficking into tissues occurs at the beginning of this phase (early morning).

The increased cytokine release at this time point therefore may exacerbate any ongoing local inflammation [24]. One of the mechanisms through which the central clock entrains peripheral tissues is by the production of glucocorticoids in the adrenal gland. Many other circadian signal transduction mediators also regulate the immune response, as melatonin and the autonomic nervous system (Fig. 1).

Perturbation of the redox rhythm (linked to the circadian clock) induced by pathogen challenge triggers immune defense genes without compromising the circadian clock [35]. Activation of innate immunity via TLR4 induces systemic inflammation by eliciting neuroendocrine and leukocyte transcriptional responses, which are regulated by the circadian clock, imposing diurnal rhythm of the inflammatory response [36]. The central clock is sensitive to immune challenge and the brain receives inflammatory signals from the periphery in response to injury/infection.

This in turn is thought to exacerbate sickness, develop symptoms like depression, and impair diurnal rhythms of temperature and melatonin secretion [36]. Melatonin, secreted by the pineal gland under SCN control, plays an important role in immune regulation; pinealectomy causes extensive immunosuppression, likely mediated by the decrease in lymphocytes and cytokines such as IL-2, IL-12, and TNF-α [35].

Sleep and light influences

The time and duration of sleep is tightly controlled by central mechanisms. These may be disrupted by disease processes, but also by other external conditions, such as night shifts, long range flight travels (jet-lag) and social nocturnal activity (social jet-lag). Pro-inflammatory cytokines are generally indicated as sleep-inducing, and basal plasma levels of these cytokines appear higher during the rest phase. Infection-associated sleepiness has been attributed to increased pro-inflammatory cytokine plasma levels [6].

Long-term sleep restriction leads to a gradual increase of circulating leukocytes and subpopulations (neutrophils, monocytes and lymphocytes) with alterations of the number and rhythm of neutrophils persisting after 1 week recovery of sleep [37]; also absolute sleep deprivation alters the rhythmicity of granulocytes [38]. Sleep disorders are one of the most common symptoms in patients with HIV/AIDS [39], but despite the circadian rhythm alteration induced by tat [40] HIV-infected patients with higher HIV Tat protein concentrations had better sleep quality, probably because it increases melatonin production, thus counteracting poor sleep quality induced by HIV [41].

On the opposite spectrum of sleep disorders, narcolepsy, which is generally considered an immune-mediated neurological disease characterized by excessive daytime sleepiness, has been recently characterized by increased inflammatory cytokine production and B and T cell activation markers [42] at variance with other hypersomnia patients who were immunologically distinct and did not present increased plasma cytokines.

Many immunological functions depend on the influence of sleep on circadian rhythms, and loss of sleep, in turn, alters the production of glucocorticoids during the night [43]. The neuroendocrine immune response of the HPA axis and sympathetic nervous system, which is activated in response to an antigenic challenge, with a transient inflammatory activity, can lead to metabolic diseases when chronically activated [44], since in all inflammatory conditions high amounts of energy have to be provided for the activated immune system. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases [8].

In patients with rheumatoid arthritis (RA), inflammation is an important covariate for the crosstalk of sleep and the HPA axis. Moreover the interrelation between sleep parameters, inflammation as objectified by C-reactive protein and serum cortisol and adrenocorticotropic hormone levels [45]. Knowledge of circadian rhythms and the influence of glucocorticoids in rheumatology is important [46]: beside optimizing treatment for the core symptoms (e.g. morning stiffness in RA), chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances [47]. Sleep and circadian disturbances are a frequent complaint of Alzheimer’s disease patients, appearing early in the course of disease, and disruption of many circadian rhythms are present also in Parkinson’s disease [48].

Physiological studies show that aging affects both sleep quality and quantity in humans, and sleep complaints increase with age [49]. Moreover, also feeding/fasting rhythms are compromised.

Circadian expression of secreted signaling molecules transmits timing information between cells and tissues. Such daily rhythms optimize energy use and temporally segregate incompatible processes.

Patients suffering from neuropsychiatric disorders often exhibit a loss of regulation of their biological rhythms which leads to alterations of sleep/wake, feeding, body temperature and hormonal rhythms. Increasing evidence indicates that the circadian system may be directly involved in the etiology of these disorders [50].

Light, especially short wavelength blue light, is the most potent environmental cue in circadian photoentrainment and lens aging is thought to influence this event by acting as a filter for shorter blue wavelengths [51]; light conditions during indoor activities as well as sunlight exposure are of paramount importance to preserve the circadian rhythmicity and avoid a risk factor for several chronic diseases. These considerations impact on the comorbidities of aged subjects, and the importance of the choice of the differential light-filtering properties of intraocular lenses after cataract removal [52].

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763605/


More information: George A. Timmons et al, The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β, Frontiers in Immunology (2021). DOI: 10.3389/fimmu.2021.700431

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