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BioRxiv : the Preprint Server For... Sep 2023Aldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The...
Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End-organ Damage.
BACKGROUND
Aldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown.
METHODS
We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5) and CCR5 knockout (CCR5) mice treated with aldosterone (600 μg/kg/day for 14 days) while receiving 1% saline to drink.
RESULTS
Here, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5 mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NFκB activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NFκB, or with Maraviroc treatment.
CONCLUSIONS
Our data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess.
PubMed: 37790434
DOI: 10.1101/2023.09.22.558020 -
Cells Sep 2023The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse... (Review)
Review
The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells. The function of CCR5 on breast cancer epithelial cells includes the induction of aberrant cell survival signaling and tropism towards chemo attractants. As CCR5 is not expressed on normal epithelium, the receptor provides a potential useful target for therapy. Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors.
PubMed: 37759462
DOI: 10.3390/cells12182237 -
Endocrinology and Metabolism (Seoul,... Oct 2023Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form...
Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.
Topics: Mice; Animals; NF-kappa B; Osteogenesis; TNF Receptor-Associated Factor 3; Ligands; Osteoclasts; Transforming Growth Factor beta
PubMed: 37749800
DOI: 10.3803/EnM.2023.501 -
Vitamins and Hormones 2023Membrane proteins such as G protein-coupled receptors (GPCRs) are involved in awide range of physiological and pathological cellular processes. Binding of extracellular...
Membrane proteins such as G protein-coupled receptors (GPCRs) are involved in awide range of physiological and pathological cellular processes. Binding of extracellular signals to GPCRs, including hormones, neurotransmitters, peptides and proteins, can activate intracellular signaling cascades via G protein interaction. Chemokine receptors are key GPCRs implicated in cancers, immune responses, cell migration and inflammation. Specifically, the CCR5 and CXCR4 chemokine receptors serve as important therapeutic targets against Human Immunodeficiency virus (HIV) entry into human cells. Maraviroc and Vicriviroc, two clinically used HIV entry inhibitors, are antagonists of the CCR5 receptor. These drugs block HIV entry, but ultimately resistance develops, due to emergence of viruses that can utilize the CXCR4 co-receptor. Unfortunately, development of chemokine receptor antagonists as selective drugs of HIV infection has been greatly hindered as their target orthosteric site is conserved among different receptor subtypes. Accordingly, it is important to understand the structural dynamics of these receptors to develop more effective therapeutics. In this chapter, we describe the latest advances in studies of these two key chemokine receptors with respect to their structures, dynamics and function.
Topics: Humans; Receptors, Chemokine; HIV Infections; Cell Movement; Inflammation; Maraviroc
PubMed: 37718001
DOI: 10.1016/bs.vh.2023.05.005 -
Molecular Oncology Jan 2024Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a...
Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5 cancer cells (ST3G5 -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid-binding Ig-like lectin 1 (CD169; also known as SIGLEC1). ST3G5 -cExos induced pro-inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial-mesenchymal transition (MMT) in PMCs, thereby generating αSMA myofibroblasts. ST3G5 -cExos also increased the expression of immune checkpoint molecules and T-cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5 -cExos upregulated chemokines, including CC-chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5 -cExo-mediated MMT, T-cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo-mediated peritoneal dissemination.
Topics: Humans; Peritoneum; Exosomes; Cell Communication; Biological Transport; Neoplasms
PubMed: 37716915
DOI: 10.1002/1878-0261.13524 -
International Immunopharmacology Nov 2023Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified....
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
PubMed: 37678029
DOI: 10.1016/j.intimp.2023.110855 -
Molecules (Basel, Switzerland) Jul 2023Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a... (Review)
Review
Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients' quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal-glial-immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.
Topics: Humans; Analgesics, Opioid; Quality of Life; Neuralgia; Neuroglia; Analgesics; Receptors, Chemokine
PubMed: 37570736
DOI: 10.3390/molecules28155766 -
Clinical Pharmacokinetics Sep 2023The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the...
BACKGROUND AND OBJECTIVE
The life expectancy of people living with HIV (PLWHIV) has significantly improved in recent decades, mostly due to antiretroviral (ARV) therapy. Aging can affect the pharmacokinetics of drugs and, as a consequence, increase the risk of drug interactions and toxicity that may impact treatment. The aim of this study was to carry out a systematic review of the literature on the effect of aging on ARV pharmacokinetics.
METHODS
Searches were performed in the BVS, EMBASE and PUBMED databases until November 2022. All studies available in English, Spanish and Portuguese investigating the pharmacokinetics of ARV approved by the US Food and Drug Administration (FDA) from 2005 to 2020 were selected. Peer-reviewed publications were included if they met all criteria: adults (≥ 18 years of age) living with or without HIV; report any pharmacokinetic parameter or plasma concentration of at least one of the following ARVs: tenofovir alafenamide fumarate (TAF); doravirine (DOR), rilpivirine (RIL) and etravirine (ETR); darunavir (DRV), tipranavir (TPV) and fostemsavir (FTR); dolutegravir (DTG), raltegravir (RAL), bictegravir (BIC) and elvitegravir (EVG); maraviroc (MVC); ibalizumab (IBA); cobicistat (COBI). Pharmacokinetic parameters were reported stratified per age group: young adults (aged 18-49 years) or older (age ≥ 50 years) and all studies were evaluated for quality. The review protocol was registered in the PROSPERO database (registration number CRD42021236432).
RESULTS
Among 97 studies included, 20 reported pharmacokinetic evaluation in older individuals (age ≥ 50 years). Twenty five percent of the articles were phase I randomized clinical trials with HIV-negative participants and non-compartmental pharmacokinetic analysis presenting the parameters area under the curve (AUC) and peak drug concentration (C). Seven age-stratified studies evaluated BIC, ETR, DRV, DTG, DOR and RAL. We found publications with discordant results for ETR and DTG pharmacokinetics in different age groups. DRV exposure was highly variable but modestly increased in aging PLWHIV. In contrast, no influence of age on BIC, DOR and RAL exposure was observed. A variability in pharmacokinetic parameters could be observed for the other ARVs (TAF and MVC) in different age groups.
CONCLUSION
Exposure to DRV increases modestly with age, while exposure to BIC, DOR and RAL appears to be unaffected by age. As the available evidence to confirm a potential effect of aging on ARV pharmacokinetics is limited, further studies are necessary.
Topics: Young Adult; Humans; Aged; Adolescent; Anti-HIV Agents; Tenofovir; Pharmaceutical Preparations; Anti-Retroviral Agents; HIV Infections; Raltegravir Potassium; Adenine; Darunavir
PubMed: 37561283
DOI: 10.1007/s40262-023-01291-x -
PloS One 2023Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration.
METHODS
We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores.
RESULTS
Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores.
CONCLUSIONS
This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis.
TRIAL REGISTRATION
Clinical trial registry: ISCRTN, registration number 31461655.
Topics: Humans; Male; Female; Non-alcoholic Fatty Liver Disease; Maraviroc; Diabetes Mellitus, Type 2; Feasibility Studies; Liver Cirrhosis; HIV Infections; Elasticity Imaging Techniques; HIV-1; Liver
PubMed: 37450478
DOI: 10.1371/journal.pone.0288598 -
AIDS (London, England) Nov 2023Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI).
DESIGN
A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5.
METHODS
Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed.
RESULTS
Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters.
CONCLUSION
This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties.
Topics: Humans; Maraviroc; HIV Infections; Cyclohexanes; Triazoles; Antiretroviral Therapy, Highly Active
PubMed: 37418541
DOI: 10.1097/QAD.0000000000003650