Figure - uploaded by Diego O Croci
Content may be subject to copyright.
a) Average amount of relative activity (see Methods for details) during each third of alpha, as determined from individual relative activity waveforms under free running conditions. b) Average waveforms for each group, adjusted to tau period. Time point 0 represents CT12. All error bars represent mean ± SEM.
Source publication
Recent evidence suggests a two-way interaction between the immune and circadian systems. Circadian control of immune factors, as well as the effect of immunological variables on circadian rhythms, might be key elements in both physiological and pathological responses to the environment. Among these relevant factors, galectin-1 is a member of a fami...
Context in source publication
Context 1
... was significantly higher in WT animals as com- pared to mutants. All data is summarized in Table 1, and representative actograms of both groups are shown in Fig. 1. A tendency towards a bimodal pattern in locomo- tor activity can be seen in mutant mice, although a three- block analysis of alpha revealed no significant differences between groups (Fig. ...Citations
... Comparison of protein abundances (logarithmized L/H ratios) in N2a cells treated with PF-670462 or DMSO showed that the majority (89%, 147 proteins) of differentially expressed proteins were upregulated in response to PF-670462 treatment, with fewer showing downregulation (11%, 19 proteins) ( Figure 1B; Table S2). Among these differentially expressed proteins were several proteins previously shown to be involved in circadian regulation and to exhibit diurnal rhythms in expression, including casein kinase 2 (Tsuchiya et al., 2009), prohibitin-2 (Kategaya et al., 2012, calreticulin (Noguchi et al., 2017), and galectin-1 (Casiraghi et al., 2010), suggesting that PF-670462 may exert effects on clock-regulated proteins through CK1δ/ε inhibition. To gain insight into the functions of the set of proteins upregulated in response to PF-670462 treatment (top cluster in Figure 1C), we performed Gene Ontology (GO) enrichment analysis and identified functional terms that were significantly overrepresented compared to a background of the accurately quantified proteins in our dataset. ...
Sleep disturbances and memory impairment are common symptoms of Alzheimer's disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. We assessed the effects of a small molecule CK1δ/ε inhibitor (PF-670462) in a cellular model of circadian clocks and in 3xTg-AD mice. Mass spectrometry-based proteomic analyses revealed that PF-670462 treatment in vitro upregulated multiple proteins that are downregulated in AD, while administration in 3xTg-AD mice reversed hippocampal proteomic alterations in diverse AD-associated and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 rescued working memory and normalized behavioural circadian rhythms in 3xTg-AD mice. Our study provides proof of concept for CK1δ/ε inhibition and direct clock modulation against AD-related proteomic changes, memory impairment, and circadian disturbances.
... Thaxton and Sharma [54] reported that IL-10 is a multifaceted agent of pregnancy. In this regard, we recently found that galectin-1, an immunoregulatory lectin which promotes immune tolerance during pregnancy by inducing IL-10 production, can also regulate murine circadian rhythmicity [55,56]. It remains to be elucidated whether TNF signaling triggers galectin-1 expression to regulate the rhythm of pregnancy-associated cytokines. ...
Objective:
Circadian rhythms are generated by the suprachiasmatic nucleus of the hypothalamus and involve rhythmic expression of clock genes and proteins. This rhythmicity is transferred to peripheral tissues by neural and hormonal signals. Late pregnancy is considered a state of inflammation which impacts on peripheral tissues such as joints. Tumor necrosis factor (TNF) mediates inflammatory and circadian responses through its p55 receptor (TNFRp55). Neuroimmunoendocrine interactions in joints have not been studied completely. The purpose of this study was to analyze these interactions, investigating the circadian rhythms of progesterone (Pg) and pro- and anti-inflammatory cytokines in the joints at the end of pregnancy (gestational day 18). Moreover, the impact of TNFRp55 deficiency on these temporal oscillations was explored.
Methods:
Wild-type and TNFRp55-deficient (KO) C57BL/6 mice were kept under constant darkness in order to study their endogenous circadian rhythms. The expression of the clock genes Bmal1 and Per1 at circadian time 7 was studied by reverse transcription polymerase chain reaction in the ankle joints of nonpregnant and pregnant (gestational day 18) mice. In late pregnancy, Pg and the cytokines interleukin 17 (IL-17), IL-6, and IL-10 were measured in the joints throughout a 24-h period by radioimmunoassay and enzyme-linked immunosorbent assay, respectively.
Results:
A significant increase in Bmal1 and Per1 mRNA expression was detected in the joints of pregnant KO mice. Furthermore, KO mice displayed a desynchronization of articular Pg and cytokine production.
Conclusions:
Our results show that TNF, via TNFRp55 signaling, modulates articular Pg and cytokine circadian rhythms in late pregnancy. These findings suggest a temporal neuroimmunoendocrine association in peripheral tissues in late pregnancy.
... Although the exact mechanisms of these functions remain to be elucidated, they appear to depend on galectin carbohydrate-binding activity and require galectin dimerization. More recently, Galectin 1 was implicated in the regulation of circadian rhythms in mice, which also points to its role in neural physiology (Casiraghi et al. 2010). Narp, a member of pentraxin family of putative endogenous lectins with structural similarity to wheat germ agglutinin, localizes to excitatory synapses and specifically clusters AMPA-type glutamate receptors (O'Brien et al. 1999). ...
Recent studies have explored the function of N-linked glycosylation in the nervous system, demonstrating essential roles of carbohydrate structures in neural development. The function of N-glycans in neural physiology remains less understood, however increasing evidence indicates that N-glycans can play specific modulatory roles controlling neural transmission and excitability of neural circuits. These roles are mediated via effects on synaptic proteins involved in neurotransmitter release, transporters that regulate nerotransmitter concentrations, neurotransmitter receptors, as well as via regulation of proteins that control excitability and response to milieu stimuli, such as voltage gated ion channels and TRP channels, respectively. Sialylated N-glycan structures are among the most potent modulators of cell excitability, exerting prominent effects on voltage gated Na(+) and K(+) channels. This modulation appears to be underlain by complex molecular mechanisms involving electrostatic effects, as well as interaction modes based on more specific steric effects and interactions with lectins and other molecules. Data also indicate that particular features of N-glycans, such as their location on a protein and structural characteristics, can be specifically associated with the effect of glycosylation. These features and their functional implications can vary between different cell types, which highlights the importance of in vivo analyses of glycan functions. Experimental challenges are associated with the overwhelming complexity of the nervous system and glycosylation pathways in vertebrates, and thus model organisms like Drosophila should help elucidate evolutionarily conserved mechanisms underlying glycan functions. Recent studies supported this notion and shed light on functions of several glycosylation genes involved in the regulation of the nervous system.
... For example, monocyte chemoattractant pro- tein-1 expression is under the control of BMAL1 in mouse macrophages, and its induction upon a LPS challenge is time dependent (Hayashi et al., 2007; Leone et al., 2012). Also, a circadian phenotype was found in mice KO for the glycan-binding protein galectin-1, suggesting a yet to be defined role in the circadian system (Casiraghi et al., 2010). There are more cues on the action of immune challenges on circadian responses. ...
Various features, components, and functions of the immune system present daily variations. Immunocompetent cell counts and cytokine levels present variations according to the time of day and the sleep-wake cycle. Moreover, different immune cell types, such as macrophages, natural killer cells, and lymphocytes, contain a circadian molecular clockwork. The biological clocks intrinsic to immune cells and lymphoid organs, together with inputs from the central pacemaker of the suprachiasmatic nuclei via humoral and neural pathways, regulate the function of cells of the immune system, including their response to signals and their effector functions. Consequences of this include, for example, the daily variation in the response to an immune challenge (e.g., bacterial endotoxin injection) and the circadian control of allergic reactions. The circadian-immune connection is bidirectional, because in addition to this circadian control of immune functions, immune challenges and immune mediators (e.g., cytokines) were shown to have strong effects on circadian rhythms at the molecular, cellular, and behavioral levels. This tight crosstalk between the circadian and immune systems has wide-ranging implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption. (Author correspondence: g.mazzoccoli@operapadrepio.it).
... Alterations in the immune system can produce changes in circadian physiology. For example, mice mutant for the Galectin-1 gene, which regulates cytokine synthesis[37], show altered free-running periods and responses to earlynight light pulses[38]. Moreover, activation of the immune system can also modulate the circadian clock. ...
Background
The relation between circadian dysregulation and cancer incidence and progression has become a topic of major interest over the last decade. Also, circadian timing has gained attention regarding the use of chronopharmacology-based therapeutics. Given its lack of functional T lymphocytes, due to a failure in thymus development, mice carrying the Foxn1(Δ/Δ) mutation (nude mice) have been traditionally used in studies including implantation of xenogeneic tumors. Since the immune system is able to modulate the circadian clock, we investigated if there were alterations in the circadian system of the athymic mutant mice.
Methods
General activity circadian rhythms in 2–4 month-old Foxn1(Δ/Δ) mice (from Swiss Webster background) and their corresponding wild type (WT) controls was recorded. The response of the circadian system to different manipulations (constant darkness, light pulses and shifts in the light–dark schedule) was analyzed.
Results
Free-running periods of athymic mice and their wild type counterpart were 23.86 ± 0.03 and 23.88 ± 0.05 hours, respectively. Both strains showed similar phase delays in response to 10 or 120 minutes light pulses applied in the early subjective night and did not differ in the number of c-Fos-expressing cells in the suprachiasmatic nuclei, after a light pulse at circadian time (CT) 15. Similarly, the two groups showed no significant difference in the time needed for resynchronization after 6-hour delays or advances in the light–dark schedule. The proportion of diurnal activity, phase-angle with the zeitgeber, subjective night duration and other activity patterns were similar between the groups.
Conclusions
Since athymic Foxn1(Δ/Δ) mice presented no differences with the WT controls in the response of the circadian system to the experimental manipulations performed in this work, we conclude that they represent a good model in studies that combine xenograft implants with either alteration of the circadian schedules or chronopharmacological approaches to therapeutics.
