Regulation of retinal photoreceptor phagocytosis in a diurnal mammal by circadian clocks and ambient lighting.
Bobu Corina,Hicks David
Investigative ophthalmology & visual science
PURPOSE:To characterize light and circadian control of photoreceptor phagocytosis in a diurnal cone-rich rodent. METHODS:Diurnal Arvicanthis ansorgei were maintained under standard cyclic light (12 hours 300 lux white light [L]/12 hours dark [D]) and were divided into five groups: 1, maintained in LD; 2, transferred to constant darkness (DD); 3, transferred to constant light (LL, 300 lux); 4, subjected to 6-hour advance in light onset; and 5, subjected to 6-hour delay in light onset. Animals were killed every 3 hours during 24 hours, and their eyes were rapidly enucleated and fixed. Cryosections were stained using specific rod (rhodopsin) and cone (MW cone opsin) antibodies. Immunopositive inclusions within the retinal pigment epithelium layer were quantified for each time point. RESULTS:In LD, both rod and cone phagocytosis showed coincident synchronized profiles with sharp peaks 1 to 2 hours after light onset. In groups 2 and 3, phagocytic activity shifted partially to the new light schedules. In DD, the temporal phagocytic profile resembled largely that of LD. On the contrary, LL animals exhibited large alterations in both rod and cone phagocytosis. There was no longer any peak, with both showing relatively uniform profiles. In addition, the number of cone phagosomes was much higher ( approximately 250% increase) compared with LD or DD. CONCLUSIONS:These data are the first to measure photoreceptor phagocytosis in a diurnal mammal under different lighting conditions and to highlight the disruptive effects of constant light, especially on cone photoreceptor function.
10.1167/iovs.08-3145
T-cell numbers and antigen-specific T-cell function follow different circadian rhythms.
Kirsch Sarah,Thijssen Stephan,Alarcon Salvador Susana,Heine Gunnar H,van Bentum Kai,Fliser Danilo,Sester Martina,Sester Urban
Journal of clinical immunology
PURPOSE:Circadian rhythms play an important role in modulating cellular immune responses. The present study was performed to characterise circadian variations in lymphocyte numbers and antigen-specific T-cell functionality in healthy individuals under physiological conditions. METHODS:Blood leukocyte populations of six healthy volunteers were quantified over 24 h. In addition, antigen-specific T-cell functionality was analysed directly ex vivo from whole blood using flow cytometry based on intracellular cytokine induction after a 6-hour stimulation with adenovirus antigen and Staphylococcus aureus enterotoxin B (SEB), respectively. RESULTS:T-cell numbers and reactivity were stable during daytime, whereas a significant increase was observed during late evening and early morning hours. The percentage of T cells reacting towards adenovirus antigen and SEB showed a 1.76 ± 0.55-fold (p = 0.0002) and a 1.42 ± 0.33-fold (p = 0.0002) increase, respectively. Dynamics in T-cell reactivity were independent of the mode of antigen stimulation and inversely correlated with plasma levels of endogenous cortisol. Interestingly, peak frequencies of reactive T cells occurred late in the evening and did not directly coincide with peak numbers of bulk T cells that were observed in the early morning hours. CONCLUSIONS:Taken together, our data reveal a circadian regulation of T-cell immune responses in the peripheral blood of humans under physiological conditions. This knowledge may be of practical consequence for the timing of blood sampling for functional T-cell assays as well as for immunosuppressive drug intake after organ transplantation, where T-cell function may be influenced not only by drug-mediated inhibition but also by circadian fluctuations in T-cell reactivity.
10.1007/s10875-012-9730-z
Immunomodulation by chronobiologically-based glucocorticoids treatment for multiple sclerosis relapses.
Glass-Marmor Lea,Paperna Tamar,Galboiz Yanna,Miller Ariel
Journal of neuroimmunology
This study compares the effects of daytime versus nighttime intravenous glucocorticoid treatment of multiple sclerosis (MS) relapses for several immune indicators. The levels of serum CRP, TNFalpha, ESR, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined at trial entry and at day 7 post therapy initiation in 35 MS patients. Serum MMP-9 protein levels were differentially affected by treatment regimen, and were significantly lower after nighttime treatment. Both treatment protocols led to a similar reduction of ESR, CRP and TNFalpha. These findings provide preliminary characterization of biomarkers in the application of chronobiology-based glucocorticoid therapeutics in MS and other immune disorders.
10.1016/j.jneuroim.2009.03.004
The cytokine MIF controls daily rhythms of symbiont nutrition in an animal-bacterial association.
Koch Eric J,Bongrand Clotilde,Bennett Brittany D,Lawhorn Susannah,Moriano-Gutierrez Silvia,Pende Marko,Vadiwala Karim,Dodt Hans-Ulrich,Raible Florian,Goldman William,Ruby Edward G,McFall-Ngai Margaret
Proceedings of the National Academy of Sciences of the United States of America
The recent recognition that many symbioses exhibit daily rhythms has encouraged research into the partner dialogue that drives these biological oscillations. Here we characterized the pivotal role of the versatile cytokine macrophage migration inhibitory factor (MIF) in regulating a metabolic rhythm in the model light-organ symbiosis between and As the juvenile host matures, it develops complex daily rhythms characterized by profound changes in the association, from gene expression to behavior. One such rhythm is a diurnal shift in symbiont metabolism triggered by the periodic provision of a specific nutrient by the mature host: each night the symbionts catabolize chitin released from hemocytes (phagocytic immune cells) that traffic into the light-organ crypts, where the population of cells resides. Nocturnal migration of these macrophage-like cells, together with identification of an MIF (EsMIF) in the light-organ transcriptome, led us to ask whether EsMIF might be the gatekeeper controlling the periodic movement of the hemocytes. Western blots, ELISAs, and confocal immunocytochemistry showed EsMIF was at highest abundance in the light organ. Its concentration there was lowest at night, when hemocytes entered the crypts. EsMIF inhibited migration of isolated hemocytes, whereas exported bacterial products, including peptidoglycan derivatives and secreted chitin catabolites, induced migration. These results provide evidence that the nocturnal decrease in EsMIF concentration permits the hemocytes to be drawn into the crypts, delivering chitin. This nutritional function for a cytokine offers the basis for the diurnal rhythms underlying a dynamic symbiotic conversation.
10.1073/pnas.2016864117
Mu opioid receptor knockout mouse: Phenotypes with implications on restless legs syndrome.
Lyu Shangru,DeAndrade Mark P,Unger Erica L,Mueller Stefan,Oksche Alexander,Walters Arthur S,Li Yuqing
Journal of neuroscience research
Restless legs syndrome (RLS) is characterized by an irresistible need to move the legs while sitting or lying at night with insomnia as a frequent consequence. Human RLS has been associated with abnormalities in the endogenous opioid system, the dopaminergic system, the iron regulatory system, anemia, and inflammatory and auto-immune disorders. Our previous work indicates that mice lacking all three subtypes of opioid receptors have a phenotype similar to that of human RLS. To study the roles of each opioid receptor subtype in RLS, we first used mu opioid receptor knockout (MOR KO) mice based on our earlier studies using postmortem brain and cell culture. The KO mice showed decreased hemoglobin, hematocrit, and red blood cells (RBCs), with an appearance of microcytic RBCs indicating anemia. Together with decreased serum iron and transferrin, but increased ferritin levels, the anemia is similar to that seen with chronic inflammation in humans. A decreased serum iron level was also observed in the wildtype mice treated with an MOR antagonist. Iron was increased in the liver and spleen of the KO mice. Normal circadian variations in the dopaminergic and serotoninergic systems were absent in the KO mice. The KO mice showed hyperactivity and increased thermal sensitivity in wakefulness primarily during what would normally be the sleep phase similar to that seen in human RLS. Deficits in endogenous opioid system transmission could predispose to anemia of inflammation and loss of circadian variations in dopaminergic or serotonergic systems, thereby contributing to an RLS-like phenotype.
10.1002/jnr.24637
Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study.
Translational psychiatry
Cortisol dysregulation, neuroinflammation, and cerebrovascular dysfunction are biological processes that have been separately shown to be affected in Alzheimer's disease (AD). Here, we aimed to identify biomarker signatures reflecting these pathways in 108 memory clinic patients with subjective cognitive decline (SCD, N = 40), mild cognitive impairment (MCI, N = 39), and AD (N = 29). Participants were from the well-characterized Cortisol and Stress in Alzheimer's Disease (Co-STAR) cohort, recruited at Karolinska University Hospital. Salivary diurnal cortisol measures and 41 CSF proteins were analyzed. Principal component analysis was applied to identify combined biosignatures related to AD pathology, synaptic loss, and neuropsychological assessments, in linear regressions adjusted for confounders, such as age, sex, education and diagnosis. We found increased CSF levels of C-reactive protein (CRP), interferon γ-inducible protein (IP-10), thymus and activation-regulated chemokine (TARC), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in MCI patients. Further, markers of cortisol dysregulation (flattened salivary cortisol awakening response and flattened cortisol slope) correlated with increased levels of placental growth factor (PlGF), IP-10, and chitinase 3-like 1 (YKL-40) in the total cohort. A biosignature composed of cortisol awakening response, cortisol slope, and CSF IL-6 was downregulated in AD patients. Moreover, biomarker signatures reflecting overlapping pathophysiological processes of neuroinflammation and vascular injury were associated with AD pathology, synaptic loss, and worsened processing speed. Our findings suggest an early dysregulation of immune and cerebrovascular processes during the MCI stage and provide insights into the interrelationship of chronic stress and neuroinflammation in AD.
10.1038/s41398-024-03072-x
Inhibition of type 1 diabetes by upregulation of the circadian rhythm-related aryl hydrocarbon receptor nuclear translocator-like 2.
He Chen-Xia,Prevot Nicolas,Boitard Christian,Avner Philip,Rogner Ute C
Immunogenetics
The genetic locus Idd6 is involved in type 1 diabetes development in the non-obese diabetic (NOD) mouse through its effect on the immune system and in particular, on T cell activities. Analysis of congenic strains for Idd6 has established the Aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) as a likely candidate gene. In this study we investigate the role of Arntl2 in the autoimmune disease and T cell activation. An Arntl2 expressing plasmid was transfected into CD4(+) T cells by nucleofection. Expression levels of cytokines and CD4(+) T cell activation markers, cell death, apoptosis, and cell proliferation rates were characterized in ex vivo experiments whilst in vivo the transfected cells were transferred into NOD.SCID mice to monitor diabetes development. The results demonstrate that Arntl2 overexpression leads to inhibition of CD4(+) T cell proliferation and decreases in their diabetogenic activity without influence on the expression levels of cytokines, CD4(+) T cell activation markers, cell death, and apoptosis. Our findings suggest that Arntl2 at the Idd6 locus may act via the inhibition of CD4(+) T cell proliferation and the reduction in the diabetogenic activity of CD4(+) T cells to protect against autoimmune type 1 diabetes in the NOD mice.
10.1007/s00251-010-0467-7
Circadian rhythmicity, variability and correlation of interleukin-6 levels in plasma and cerebrospinal fluid of healthy men.
Agorastos Agorastos,Hauger Richard L,Barkauskas Donald A,Moeller-Bertram Tobias,Clopton Paul L,Haji Uzair,Lohr James B,Geracioti Thomas D,Patel Piyush M,Chrousos George P,Baker Dewleen G
Psychoneuroendocrinology
BACKGROUND:Interleukin-6 (IL-6) is a cytokine with pleiotropic actions in both the periphery of the body and the central nervous system (CNS). Altered IL-6 secretion has been associated with inflammatory dysregulation and several adverse health consequences. However, little is known about the physiological circadian characteristics and dynamic inter-correlation between circulating and CNS IL-6 levels in humans, or their significance. METHODS:Simultaneous assessment of plasma and cerebrospinal fluid (CSF) IL-6 levels was performed hourly in 11 healthy male volunteers over 24h, to characterize physiological IL-6 secretion levels in both compartments. RESULTS:IL-6 levels showed considerable within- and between-subject variability in both plasma and CSF, with plasma/CSF ratios revealing consistently higher levels in the CSF. Both CSF and plasma IL-6 levels showed a distinctive circadian variation, with CSF IL-6 levels exhibiting a main 24h, and plasma a biphasic 12h, circadian component. Plasma peaks were roughly at 4 p.m. and 4 a.m., while the CSF peak was at around 7 p.m. There was no correlation between coincident CSF and plasma IL-6 values, but evidence for significant correlations at a negative 7-8h time lag. CONCLUSIONS:This study provides evidence in humans for a circadian IL-6 rhythm in CSF and confirms prior observations reporting a plasma biphasic circadian pattern. Our results indicate differential IL-6 regulation across the two compartments and are consistent with local production of IL-6 in the CNS. Possible physiological significance is discussed and implications for further research are highlighted.
10.1016/j.psyneuen.2014.02.020
Environmental disruption of the circadian clock leads to altered sleep and immune responses in mouse.
Phillips Derrick J,Savenkova Marina I,Karatsoreos Ilia N
Brain, behavior, and immunity
In mammals, one of the most salient outputs of the circadian (daily) clock is the timing of the sleep-wake cycle. Modern industrialized society has led to a fundamental breakdown in the relationship between our endogenous timekeeping systems and the solar day, disrupting normal circadian rhythms. We have argued that disrupted circadian rhythms could lead to changes in allostatic load, and the capacity of organisms to respond to other environmental challenges. In this set of studies, we apply a model of circadian disruption characterized in our lab in which mice are housed in a 20h long day, with 10h of light and 10h of darkness. We explored the effects of this environmental disruption on sleep patterns, to establish if this model results in marked sleep deprivation. Given the interaction between circadian, sleep, and immune systems, we further probed if our model of circadian disruption also alters the innate immune response to peripheral bacterial endotoxin challenge. Our results demonstrate that this model of circadian disruption does not lead to marked sleep deprivation, but instead affects the timing and quality of sleep. We also show that while circadian disruption does not lead to basal changes in the immune markers we explored, the immune response is affected, both in the brain and the periphery. Together, our findings further strengthen the important role of the circadian timing system in sleep regulation and immune responses, and provide evidence that disrupting the circadian clock increases vulnerability to further environmental stressors, including immunological challenges.
10.1016/j.bbi.2014.12.008
Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice.
Inokawa Hitoshi,Umemura Yasuhiro,Shimba Akihiro,Kawakami Eiryo,Koike Nobuya,Tsuchiya Yoshiki,Ohashi Munehiro,Minami Yoichi,Cui Guangwei,Asahi Takuma,Ono Ryutaro,Sasawaki Yuh,Konishi Eiichi,Yoo Seung-Hee,Chen Zheng,Teramukai Satoshi,Ikuta Koichi,Yagita Kazuhiro
Scientific reports
Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1CD44 CD4 T cells as well as CD95GL7 germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
10.1038/s41598-020-59541-y
A study on circadian rhythm disorder of rat lung tissue caused by mechanical ventilation induced lung injury.
Li Huan,Wang Chunxiao,Hu Jiaqi,Tan Junyuan
International immunopharmacology
Ventilator-induced lung injury (VILI), the most serious complication of mechanical ventilation therapy, is an excessive inflammatory response in lung tissue characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators. The pathogenesis of VILI is very complex. It is becoming increasingly evident that disruption of circadian rhythm affects the immune response. Whether the pathogenesis of VILI is associated with circadian rhythm disruption has not been reported. In this study, we establish VILI model in SD rat by performing an endotracheal intubation and placing the rat on a mechanical ventilator (tidal volume of 40 ml/kg or 10 ml/kg without positive end-expiratory pressure). To examine the effect of VILI on clock gene expression, real-time quantitative PCR was performed to measure bmal1, clock, per2 and Rev-erbα mRNA expression. We found that Rev-erbα mRNA was significantly decreased in high tide volume mechanical ventilation group compared with spontaneous group, the same as REV-ERBα protein product which was tested by Western blot approach. Stimulation of REV-ERBα activity by SR9009 greatly diminished VILI-induced lung edema, inflammatory cell infiltration and the production of the pro-inflammatory cytokine TNF-α. Collectively, our findings are the first to show that REV-ERBα plays an important role in VILI and inflammation, and circadian rhythm disorder in inflammation response may be a novel pathogenesis of VILI.
10.1016/j.intimp.2013.12.001
Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis.
Cellular and molecular gastroenterology and hepatology
BACKGROUND & AIMS:Alcohol intake with circadian rhythm disruption (CRD) increases colon cancer risk. We hypothesized that eating during or around physiologic rest time, a common habit in modern society, causes CRD and investigated the mechanisms by which it promotes alcohol-associated colon carcinogenesis. METHODS:The effect of feeding time on CRD was assessed using B6 mice expressing a fusion protein of PERIOD2 and LUCIFERASE (PER2::LUC) were used to model colon polyposis and to assess the effects of feeding schedules, alcohol consumption, and prebiotic treatment on microbiota composition, short-chain fatty acid levels, colon inflammation, and cancer risk. The relationship between butyrate signaling and a proinflammatory profile was assessed by inactivating the butyrate receptor GPR109A. RESULTS:Eating at rest (wrong-time eating [WTE]) shifted the phase of the colon rhythm in PER2::LUC mice. In TS4Cre × APC mice, a combination of WTE and alcohol exposure (WTE + alcohol) decreased the levels of short-chain fatty acid-producing bacteria and of butyrate, reduced colonic densities of regulatory T cells, induced a proinflammatory profile characterized by hyperpermeability and an increased mucosal T-helper cell 17/regulatory T cell ratio, and promoted colorectal cancer. Prebiotic treatment improved the mucosal inflammatory profile and attenuated inflammation and cancer. WTE + alcohol-induced polyposis was associated with increased signal transducer and activator of transcription 3 expression. Decreased butyrate signaling activated the epithelial signal transducer and activator of transcription 3 in vitro. The relationship between butyrate signaling and a proinflammatory profile was confirmed in human colorectal cancers using The Cancer Genome Atlas. CONCLUSIONS:Abnormal timing of food intake caused CRD and interacts with alcohol consumption to promote colon carcinogenesis by inducing a protumorigenic inflammatory profile driven by changes in the colon microbiota and butyrate signaling. Accession number of repository for microbiota sequence data: raw FASTQ data were deposited in the NCBI Sequence Read Archive under project PRJNA523141.
10.1016/j.jcmgh.2019.10.011
Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes.
Diabetologia
AIMS/HYPOTHESIS:The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. METHODS:Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18-40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. RESULTS:Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. CONCLUSIONS/INTERPRETATION:Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation.
10.1007/s00125-021-05468-6
gene circannual expression in cluster headache.
Cephalalgia : an international journal of headache
BACKGROUND:Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The gene has a central role in regulating circadian rhythms. Here, we investigate the circannual expression in a population of cluster headache patients in comparison to matched controls. METHODS:Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS:This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to expression. CONCLUSIONS:We observed that expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence expression.
10.1177/03331024241247845
Circadian regulation of human peripheral neutrophils.
Brain, behavior, and immunity
Neutrophils are the most abundant leukocytes in human blood. Beside being essential responders in bacterial and fungal infections, they also contribute to tissue reactions in many autoimmune and inflammatory diseases. Although several immune responses linked to neutrophil functions have been described to be rhythmic, the mechanism of the circadian regulation of these cells is still not understood. Characterization of the time-of-day-specific control of neutrophil responsiveness could help to better understand the pathomechanism of these inflammatory responses and design effective chronotherapy. Here we report that the time-dependent expression of core clock components in human neutrophils characteristically differs from that in mononuclear cells. Both the low expression and the reduced nuclear accumulation of the essential clock protein BMAL1 suggest that the molecular oscillator is down-regulated in neutrophils. By following the expression of the maturation marker Cxcr4 and morphological attributes (side-scattering properties and nuclear segmentation), we found that the distribution of young and aged cells within the peripheral neutrophil pool displays a daily rhythm. In addition, we detected synchronous fluctuations in the plasma level of the CXCR4 ligand CXCL12, an important regulator of cell trafficking within the bone marrow. We found that expression of another maturation marker, the core component of the superoxide generating NADPH oxidase, and parallelly, the superoxide producing capacity of neutrophils were also dependent on the time of the day. In line with this, number of opsonized bacteria engulfed by neutrophils also showed time-dependent differences, supporting that clearance of pathogens shows a daily rhythm. We suggest that maturation-dependent changes in neutrophil responsiveness rather than the cellular autonomous clock are involved in the daily regulation of human neutrophil functions.
10.1016/j.bbi.2016.04.016
Modulation of behavior by the histaminergic system: lessons from HDC-, H3R- and H4R-deficient mice.
Schneider Erich H,Neumann Detlef,Seifert Roland
Neuroscience and biobehavioral reviews
Histamine, which is synthesized by histidine decarboxylase (HDC), does not only modulate the immune system, but is also acting as a neurotransmitter. Histaminergic neurons project from the tuberomamillary nucleus to numerous brain regions. Activation of presynaptic H3R inhibits the release of histamine and of non-histaminergic neurotransmitters. The phenotypes of Hdc(-/-)- and Hrh3(-/-) mice comprise behaviors related to locomotor activity, memory, cognition, anxiety, circadian rhythm, pain perception, food intake and addiction. We critically discuss these phenotypes that are probably caused by global changes of the histaminergic tone rather than by an altered stimulation of a single histamine receptor subtype. Constitutive H3R activity may add another layer of complexity by causing "histamine-independent histaminergic" processes, e.g. in Hdc(-/-) mice. We also discuss the clinical relevance of H3R- and HDC-deficient mice, e.g. the role of HDC in Tourette's syndrome. Finally, this review summarizes current knowledge on possible central H4R functions. Neuronal expression of H4R, however, is discussed controversially and a systematic behavioral characterization of Hrh4(-/-) mice is still missing.
10.1016/j.neubiorev.2014.07.020
Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.
Journal of Alzheimer's disease : JAD
Sleep dysfunction has been identified in the pathophysiology of Alzheimer's disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.
10.3233/JAD-201573
Cell-type and sex-specific rhythmic gene expression in the nucleus accumbens.
Molecular psychiatry
Circadian rhythms are critical for human health and are highly conserved across species. Disruptions in these rhythms contribute to many diseases, including psychiatric disorders. Previous results suggest that circadian genes modulate behavior through specific cell types in the nucleus accumbens (NAc), particularly dopamine D1-expressing medium spiny neurons (MSNs). However, diurnal rhythms in transcript expression have not been investigated in NAc MSNs. In this study we identified and characterized rhythmic transcripts in D1- and D2-expressing neurons and compared rhythmicity results to homogenate as well as astrocyte samples taken from the NAc of male and female mice. We find that all cell types have transcripts with diurnal rhythms and that top rhythmic transcripts are largely core clock genes, which peak at approximately the same time of day in each cell type and sex. While clock-controlled rhythmic transcripts are enriched for protein regulation pathways across cell type, cell signaling and signal transduction related processes are most commonly enriched in MSNs. In contrast to core clock genes, these clock-controlled rhythmic transcripts tend to reach their peak in expression about 2-h later in females than males, suggesting diurnal rhythms in reward may be delayed in females. We also find sex differences in pathway enrichment for rhythmic transcripts peaking at different times of day. Protein folding and immune responses are enriched in transcripts that peak in the dark phase, while metabolic processes are primarily enriched in transcripts that peak in the light phase. Importantly, we also find that several classic markers used to categorize MSNs are rhythmic in the NAc. This is critical since the use of rhythmic markers could lead to over- or under-enrichment of targeted cell types depending on the time at which they are sampled. This study greatly expands our knowledge of how individual cell types contribute to rhythms in the NAc.
10.1038/s41380-024-02569-7
Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy.
Cancer immunology, immunotherapy : CII
BACKGROUND:While epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy. METHODS:Based on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response. RESULTS:The cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8 T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of "hot" immunophenotype. CONCLUSION:In a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.
10.1007/s00262-023-03495-3
Regulates the Daily Timing of Colitis.
Frontiers in cellular and infection microbiology
Many physiological functions exhibit circadian rhythms: oscillations in biological processes that occur in a 24-hour period. These daily rhythms are maintained through a highly conserved molecular pacemaker known as the circadian clock. Circadian disruption has been proposed to cause increased risk of Inflammatory Bowel Disease (IBD) but the underlying mechanisms remain unclear. Patients with IBD experience chronic inflammation and impaired regeneration of intestinal epithelial cells. Previous animal-based studies have revealed that colitis models of IBD are more severe in mice without a circadian clock but the timing of colitis, and whether its inflammatory and regenerative processes have daily rhythms, remains poorly characterized. We tested circadian disruption using mutant mice that have a non-functional circadian clock and thus no circadian rhythms. Dextran Sulfate Sodium (DSS) was used to induce colitis. The disease activity of colitis was found to exhibit time-dependent variation in control mice but is constant and elevated in mutants, who exhibit poor recovery. Histological analyses indicate worsened colitis severity in mutant colon, and colon infiltration of immune system cells shows a daily rhythm that is lost in the mutant. Similarly, epithelial proliferation in the colon has a daily rhythm in controls but not in mutants. Our results support a critical role of a functional circadian clock in the colon which drives 24-hour rhythms in inflammation and healing, and whose disruption impairs colitis recovery. This indicates that weakening circadian rhythms not only worsens colitis, but delays healing and should be taken into account in the management of IBD. Recognition of this is important in the management of IBD patients required to do shift work.
10.3389/fcimb.2022.773413