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Nature Oct 2023CD8 T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However,...
CD8 T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Although it is clear that chronic antigen contributes to CD8 T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β-adrenergic receptor ADRB1. We identify that exhausted CD8 T cells increase ADRB1 expression and that exposure of ADRB1 T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8 T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8 T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8 T cells rejuvenates anti-tumour functions.
Topics: Humans; Antigens; Catecholamines; CD8-Positive T-Lymphocytes; Cell Proliferation; Immune Checkpoint Inhibitors; Melanoma; Memory T Cells; Pancreatic Neoplasms; Receptors, Adrenergic, beta-1; Sympathetic Nervous System; T-Cell Exhaustion; Stress, Physiological
PubMed: 37731001
DOI: 10.1038/s41586-023-06568-6 -
Cell Metabolism Aug 2023Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight...
Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight loss is unknown. Obese rats were treated with GDF15 and displayed increased insulin tolerance 5 h later. Lean and obese female and male mice were treated with GDF15 on days 1, 3, and 5 without weight loss and displayed increased insulin sensitivity during a euglycemic hyperinsulinemic clamp on day 6 due to enhanced suppression of endogenous glucose production and increased glucose uptake in WAT and BAT. GDF15 also reduced glucagon levels during clamp independently of the GFRAL receptor. The insulin-sensitizing effect of GDF15 was completely abrogated in GFRAL KO mice and also by treatment with the β-adrenergic antagonist propranolol and in β1,β2-adrenergic receptor KO mice. GDF15 activation of the GFRAL receptor increases β-adrenergic signaling, in turn, improving insulin action in the liver and white and brown adipose tissue.
Topics: Mice; Rats; Male; Female; Animals; Receptors, Adrenergic, beta; Growth Differentiation Factor 15; Obesity; Adipose Tissue; Weight Loss; Insulin; Adipose Tissue, Brown; Liver; Insulin Resistance
PubMed: 37473755
DOI: 10.1016/j.cmet.2023.06.016 -
Nature Jul 2023Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with...
Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.
Topics: Animals; Humans; Mice; Appetite Depressants; Caloric Restriction; Diabetes Mellitus, Type 2; Diet, High-Fat; Eating; Energy Metabolism; Growth Differentiation Factor 15; Muscle, Skeletal; Non-alcoholic Fatty Liver Disease; Receptors, Adrenergic, beta; Weight Loss
PubMed: 37380764
DOI: 10.1038/s41586-023-06249-4 -
Science (New York, N.Y.) Dec 2023Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses...
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) bind to extracellular ligands and drugs and modulate intracellular responses through conformational changes. Despite their importance as drug targets, the molecular origins of pharmacological properties such as efficacy (maximum signaling response) and potency (the ligand concentration at half-maximal response) remain poorly understood for any ligand-receptor-signaling system. We used the prototypical adrenaline-β2 adrenergic receptor-G protein system to reveal how specific receptor residues decode and translate the information encoded in a ligand to mediate a signaling response. We present a data science framework to integrate pharmacological and structural data to uncover structural changes and allosteric networks relevant for ligand pharmacology. These methods can be tailored to study any ligand-receptor-signaling system, and the principles open possibilities for designing orthosteric and allosteric compounds with defined signaling properties.
Topics: Humans; Adrenergic beta-2 Receptor Agonists; Allosteric Regulation; Biosensing Techniques; Ligands; Protein Conformation; Receptors, Adrenergic, beta-2; Signal Transduction; Bioluminescence Resonance Energy Transfer Techniques
PubMed: 38127743
DOI: 10.1126/science.adh1859 -
Nature Nov 2023Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI). Noradrenaline levels are increased after TBI, and the amplitude of the...
Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI). Noradrenaline levels are increased after TBI, and the amplitude of the increase in noradrenaline predicts both the extent of injury and the likelihood of mortality. Glymphatic impairment is both a feature of and a contributor to brain injury, but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.
Topics: Animals; Mice; Adrenergic Antagonists; Brain Edema; Brain Injuries, Traumatic; Disease Models, Animal; Glymphatic System; Inflammation; Lymphatic Vessels; Norepinephrine; Phosphorylation; Receptors, Adrenergic
PubMed: 37968397
DOI: 10.1038/s41586-023-06737-7 -
Circulation Nov 2023Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor...
BACKGROUND
Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.
METHODS
We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM ( and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM ().
RESULTS
We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in iPSC-derived cardiomyocytes.
CONCLUSIONS
R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.
Topics: Humans; Mice; Animals; Carvedilol; Metoprolol; Ryanodine Receptor Calcium Release Channel; Cardiomyopathy, Hypertrophic; Arrhythmias, Cardiac; Adrenergic beta-Antagonists; Myocytes, Cardiac; Verapamil; Receptors, Adrenergic
PubMed: 37850394
DOI: 10.1161/CIRCULATIONAHA.123.065017