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Retrovirology Aug 2021The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling... (Review)
Review
The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.
Topics: Animals; CCR5 Receptor Antagonists; Clinical Trials as Topic; HIV Infections; HIV-1; Humans; Mice; Neuroinflammatory Diseases; Receptors, CCR5; Receptors, CXCR4; Receptors, HIV; Signal Transduction
PubMed: 34429135
DOI: 10.1186/s12977-021-00569-x -
The Journal of Allergy and Clinical... Jul 2023Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear.
BACKGROUND
Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear.
OBJECTIVE
We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation.
METHODS
CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1 murine severe asthma model.
RESULTS
Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5 participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1/T2/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation.
CONCLUSION
CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.
Topics: Animals; Humans; Mice; Asthma; Chemokine CCL5; Chemokines; Eosinophils; Inflammation; Neutrophils; Sputum
PubMed: 36893862
DOI: 10.1016/j.jaci.2023.02.028 -
Immunity, Inflammation and Disease Sep 2022The C-C chemokine receptor 5 (CCR5) is mainly expressed in a variety of immune cells. It interacts with multiple chemokine ligands that mediate the trafficking and... (Review)
Review
BACKGROUND
The C-C chemokine receptor 5 (CCR5) is mainly expressed in a variety of immune cells. It interacts with multiple chemokine ligands that mediate the trafficking and recruitment of effector cells toward sites of inflammation. CCR5 not only plays a critical role in cell growth, activation, differentiation, adhesion, and migration but also participates in the development of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation.
METHODS
This is a literature review article. The research design method is an evidence-based rapid review. The present discourse aim is first to scrutinize and assess the available literature on CCR5 and acute GVHD. Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed.
RESULTS
CCR5 is a marker of GVHD effector cells, and CCR5 expression is elevated when acute GVHD occurs. CCR5 blockade with maraviroc in clinical trials results in a low incidence of acute GVHD. The immune mechanism includes that CCR5 blockade inhibits donor T cell migration and recruitment toward target organs, reduces the absolute numbers of donor T cells, is capable of slightly suppressing dendritic cell maturation, and reduces the percentage of Th1 and Th17 subsets. CCR5 blockade also inhibits internalization and activation of chemokines, inhibits proliferation and chemotaxis of T cells, and decreases the production of TNF-α and IFN-γ. In addition, there may be a form of crosstalk between CCR5 and CCR2. Inconsistently, infusion of CCR5 Tregs into lethally irradiated mice significantly increased the infiltration of CD4 and CD8 T cells into the liver, resulting in earlier and more severe GVHD.
CONCLUSION
This review indicates that CCR5 plays an important role in pathogenesis and development of acute GVHD. Elucidating its role in different immune cells will aid the development of targeted therapeutic treatments.
Topics: Animals; CD8-Positive T-Lymphocytes; Chemokines; Chemokines, CC; Graft vs Host Disease; Maraviroc; Mice; Receptors, CCR5
PubMed: 36039647
DOI: 10.1002/iid3.687 -
Advanced Science (Weinheim,... Nov 2023There is no effective therapy for ischemic stroke following the acute stage. Neural transplantation offers a potential option for repairing the ischemic lesion. However,...
There is no effective therapy for ischemic stroke following the acute stage. Neural transplantation offers a potential option for repairing the ischemic lesion. However, this strategy is hindered by the poor survival of the neural precursor cells (NPCs) that are transplanted into the inflammatory ischemic core. Here, a chemical cocktail consisting of fibrinogen and maraviroc is developed to promote the survival of the transplanted NPCs in the ischemic core of the mouse cerebral cortex. The grafted NPCs survive in the presence of the cocktail but not fibrinogen or maraviroc alone at day 7. The surviving NPCs divide and differentiate to mature neurons by day 30, reconstituting the infarct cortex with vascularization. Molecular analysis in vivo and in vitro shows that blocking the activation of CCR5 on the NPCs protects the NPCs from apoptosis induced by pro-inflammatory factors, revealing the underlying protective effect of the cocktail for NPCs. The findings open an avenue to enable survival of the transplanted NPCs under the inflammatory neurological conditions like stroke.
Topics: Mice; Animals; Neural Stem Cells; Maraviroc; Cell Differentiation; Brain; Neurons
PubMed: 37867250
DOI: 10.1002/advs.202302527 -
Cell Reports Nov 2023Paclitaxel leads to peripheral neuropathy (paclitaxel-induced peripheral neuropathy [PIPN]) in approximately 50% of cancer patients. At present, there are no effective...
Paclitaxel leads to peripheral neuropathy (paclitaxel-induced peripheral neuropathy [PIPN]) in approximately 50% of cancer patients. At present, there are no effective treatment strategies for PIPN, the mechanisms of which also remain unclear. In this study, we performed microbiome and metabolome analysis of feces and serum from breast cancer patients with different PIPN grades due to paclitaxel treatment. Our analysis reveals that levels of deoxycholic acid (DCA) are highly increased because of ingrowth of Clostridium species, which is associated with severe neuropathy. DCA, in turn, elevates serum level of C-C motif ligand 5 (CCL5) and induces CCL5 receptor 5 (CCR5) overexpression in dorsal root ganglion (DRG) through the bile acid receptor Takeda G-protein-coupled receptor 5 (TGR5), contributing to neuronal hyperexcitability. Consistent with this, administration of CCR5 antagonist maraviroc suppresses the development of neuropathic nociception. These results implicate gut microbiota/bile acids/CCR5 signaling in the induction of PIPN, thus suggesting a target for PIPN treatment.
Topics: Humans; Female; Paclitaxel; Neuralgia; Breast Neoplasms; Maraviroc; Deoxycholic Acid; Receptors, CCR5
PubMed: 37948181
DOI: 10.1016/j.celrep.2023.113386 -
Molecular Neurodegeneration Nov 2021Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer's Disease (AD)-like brain pathologies, including increased...
BACKGROUND
Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer's Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies.
METHODS
NOD/scid-IL-2Rγ mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal's blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA.
RESULTS
HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor-related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist.
CONCLUSIONS
Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Endothelial Cells; Mice; Mice, Inbred NOD; Receptor for Advanced Glycation End Products
PubMed: 34809709
DOI: 10.1186/s13024-021-00500-0 -
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 -
Journal of Neuroinflammation Jul 2022Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score,...
BACKGROUND
Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear.
METHODS
Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks.
RESULTS
Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C-C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure.
CONCLUSION
These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.
Topics: Animals; Autism Spectrum Disorder; Behavior, Animal; Disease Models, Animal; Female; Maraviroc; Mice; Minocycline; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, CCR5; Valproic Acid
PubMed: 35906621
DOI: 10.1186/s12974-022-02559-y -
Advances in Cancer Research 2020The G coupled protein receptor CC chemokine receptor type 5 (CCR5) has the unusual characteristic in humans of being a developmentally non-essential gene that... (Review)
Review
The G coupled protein receptor CC chemokine receptor type 5 (CCR5) has the unusual characteristic in humans of being a developmentally non-essential gene that participates in several pathological processes including infection with HIV (Dean et al., 1996; Gupta et al., 2019; Samson et al., 1996), progression of stroke (Joy et al., 2019), osteoporosis (Xie et al., 2019) and the metastasis of cancer (Jiao et al., 2018; Velasco-Velazquez et al., 2012, 2014) (Reviewed in: Jiao, Nawab, et al., 2019; Jiao, Wang, & Pestell, 2019). The importance of CCR5 in HIV led to recent genetic engineering of humans to recreate a non-functional CCR5 gene. Thus, although the application of gene-editing tools, to manipulate human embryos is prohibited in the United States, and China. at the Second International Summit on Human Genome Editing in Hong Kong (http://www.nationalacademies.org/), it was claimed that CRISPR-Cas9 systems had been used to edit the CCR5 gene in twin baby girls. The importance of CCR5 in stroke has led to clinical trials using maraviroc (NCT03172026). The key function of CCR5 in cancer metastasis and homing (Jiao et al., 2018; Jiao, Nawab, et al., 2019; Velasco-Velazquez et al., 2012, 2014) has led to three active clinical trials for metastatic cancer using CCR5 antagonists (Jiao, Nawab, et al., 2019; Jiao, Wang, & Pestell, 2019). Thus, it was surprising to find that the all-cause mortality rate in individuals who are homozygous for the CCR5△32 allele in the United Kingdom normal population was increased >20% increase, with an almost 2 year reduction overall lifespan (Wei & Nielsen, 2019). The current review herein discusses the distinct functions of CCR5 in human disease and potential avenues for further research.
Topics: Humans; Neoplasm Metastasis; Neoplasms; Receptors, CCR5; Signal Transduction
PubMed: 32089164
DOI: 10.1016/bs.acr.2019.11.001 -
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