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1.
Sheng Li Xue Bao ; 76(3): 429-437, 2024 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-38939937

RESUMO

As a multifunctional adipokine, chemerin plays a crucial role in various pathophysiological processes through endocrine and paracrine manner. It can bind to three known receptors (ChemR23, GPR1 and CCRL2) and participate in energy metabolism, glucose and lipid metabolism, and inflammation, especially in metabolic diseases. Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases, which seriously affects the normal life of women of childbearing age. Patients with PCOS have significantly increased serum levels of chemerin and high expression of chemerin in their ovaries. More and more studies have shown that chemerin is involved in the occurrence and development of PCOS by affecting obesity, insulin resistance, hyperandrogenism, oxidative stress and inflammatory response. This article mainly reviews the production, subtypes, function and receptors of chemerin protein, summarizes and discusses the research status of chemerin protein in PCOS from the perspectives of metabolism, reproduction and inflammation, and provides theoretical basis and reference for the clinical diagnosis and treatment of PCOS.


Assuntos
Quimiocinas , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome do Ovário Policístico , Síndrome do Ovário Policístico/metabolismo , Humanos , Quimiocinas/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Receptores de Quimiocinas/metabolismo , Resistência à Insulina , Animais , Receptores Acoplados a Proteínas G/metabolismo , Fatores Quimiotáticos/metabolismo
2.
Biochem Soc Trans ; 52(3): 1011-1024, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38856028

RESUMO

Chemokine receptors are integral to the immune system and prime targets in drug discovery that have undergone extensive structural elucidation in recent years. We outline a timeline of these structural achievements, discuss the intracellular negative allosteric modulation of chemokine receptors, analyze the mechanisms of orthosteric receptor activation, and report on the emerging concept of biased signaling. Additionally, we highlight differences of G-protein binding among chemokine receptors. Intracellular allosteric modulators in chemokine receptors interact with a conserved motif within transmembrane helix 7 and helix 8 and exhibit a two-fold inactivation mechanism that can be harnessed for drug-discovery efforts. Chemokine recognition is a multi-step process traditionally explained by a two-site model within chemokine recognition site 1 (CRS1) and CRS2. Recent structural studies have extended our understanding of this complex mechanism with the identification of CRS1.5 and CRS3. CRS3 is implicated in determining ligand specificity and surrounds the chemokine by almost 180°. Within CRS3 we identified the extracellular loop 2 residue 45.51 as a key interaction mediator for chemokine binding. Y2917.43 on the other hand was shown in CCR1 to be a key determinant of signaling bias which, along with specific chemokine-dependent phosphorylation ensembles at the G-protein coupled receptors (GPCR's) C-terminus, seems to play a pivotal role in determining the direction of signal bias in GPCRs.


Assuntos
Receptores de Quimiocinas , Transdução de Sinais , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/química , Humanos , Quimiocinas/metabolismo , Quimiocinas/química , Ligação Proteica , Regulação Alostérica , Modelos Moleculares , Animais , Sítios de Ligação , Conformação Proteica , Ligantes
3.
Life Sci Alliance ; 7(8)2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38782603

RESUMO

It is known that stress influences immune cell function. The underlying molecular mechanisms are unclear. We recently reported that many chemokine receptors (CRs) heteromerize with α1-adrenoceptors (α1-ARs) through which CRs are regulated. Here, we show that arginine vasopressin receptor 1A (AVPR1A) heteromerizes with all human CRs, except chemokine (C-X-C motif) receptor (CXCR)1, in recombinant systems and that such heteromers are detectable in THP-1 cells and human monocytes. We demonstrate that ligand-free AVPR1A differentially regulates the efficacy of CR partners to mediate chemotaxis and that AVPR1A ligands disrupt AVPR1A:CR heteromers, which enhances chemokine (C-C motif) receptor (CCR)1-mediated chemotaxis and inhibits CCR2-, CCR8-, and CXCR4-mediated chemotaxis. Using bioluminescence resonance energy transfer to monitor G protein activation and CRISPR/Cas9 gene-edited THP-1 cells lacking AVPR1A or α1B-AR, we show that CRs that share the propensity to heteromerize with α1B/D-ARs and AVPR1A exist and function within interdependent hetero-oligomeric complexes through which the efficacy of CRs to mediate chemotaxis is controlled. Our findings suggest that hetero-oligomers composed of CRs, α1B/D-ARs, and AVPR1A may enable stress hormones to regulate immune cell trafficking.


Assuntos
Quimiotaxia , Monócitos , Receptores de Quimiocinas , Receptores de Vasopressinas , Humanos , Monócitos/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Receptores de Vasopressinas/metabolismo , Receptores de Vasopressinas/genética , Células THP-1 , Multimerização Proteica , Células HEK293 , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Sistemas CRISPR-Cas , Transdução de Sinais , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/genética , Ligantes
4.
Mech Ageing Dev ; 220: 111944, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38782074

RESUMO

Age-related inflammation or inflammaging is a critical deciding factor of physiological homeostasis during aging. Cardiovascular diseases (CVDs) are exquisitely associated with aging and inflammation and are one of the leading causes of high mortality in the elderly population. Inflammaging comprises dysregulation of crosstalk between the vascular and cardiac tissues that deteriorates the vasculature network leading to development of atherosclerosis and atherosclerotic-associated CVDs in elderly populations. Leukocyte differentiation, migration and recruitment holds a crucial position in both inflammaging and atherosclerotic CVDs through relaying the activity of an intricate network of inflammation-associated protein-protein interactions. Among these interactions, small immunoproteins such as chemokines play a major role in the progression of inflammaging and atherosclerosis. Chemokines are actively involved in lymphocyte migration and severe inflammatory response at the site of injury. They relay their functions via chemokine-G protein-coupled receptors-glycosaminoglycan signaling axis and is a principal part for the detection of age-related atherosclerosis and related CVDs. This review focuses on highlighting the detailed intricacies of the effects of chemokine-receptor interaction and chemokine oligomerization on lymphocyte recruitment and its evident role in clinical manifestations of atherosclerosis and related CVDs. Further, the role of chemokine mediated signaling for formulating next-generation therapeutics against atherosclerosis has also been discussed.


Assuntos
Envelhecimento , Aterosclerose , Quimiocinas , Inflamação , Humanos , Aterosclerose/metabolismo , Aterosclerose/imunologia , Envelhecimento/metabolismo , Envelhecimento/imunologia , Inflamação/metabolismo , Inflamação/imunologia , Quimiocinas/metabolismo , Animais , Transdução de Sinais , Receptores de Quimiocinas/metabolismo
5.
Front Immunol ; 15: 1345381, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38736890

RESUMO

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4ß7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-ß, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-ß receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.


Assuntos
Quimiocinas , Síndrome de Sjogren , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Humanos , Quimiocinas/metabolismo , Quimiocinas/imunologia , Transdução de Sinais , Animais , Receptores de Retorno de Linfócitos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/imunologia
6.
Int Immunopharmacol ; 134: 112172, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38703566

RESUMO

BACKGROUND: The clinical significance and comprehensive characteristics of chemokines and chemokine receptors in colorectal cancer (CRC) have not been previously reported. Our study aims to investigate the expression profiles of chemokines and chemokine receptors, as well as establish subtypes in CRC. METHODS: 1009 CRC samples were enrolled in our study. Consensus unsupervised clustering analysis was conducted to establish subtypes, and a risk score model was developed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. 36 pairs of tissue specimens of CRC patients and two CRC cell lines were used to validate the subtypes and risk score in vitro. Quantitative real-time PCR and western blotting were employed to validate mRNA and protein expression levels, respectively. Flow cytometry was utilized for analyzing cell apoptosis, while cell viability assay and EdU assay were conducted to assess cell proliferation ability. RESULTS: The Cluster B group shares similarities with the low-risk group in terms of exhibiting a higher level of immune cell infiltration and belonging to hot tumor. Patients CRC in the Cluster B group demonstrate a more favorable prognosis and exhibit better response to immunotherapy and chemotherapy. On the other hand, the Cluster A group resembles the high-risk group as it displays lower levels of immune cell infiltration, indicating a cold tumor phenotype. CRC patients in the Cluster A group have poorer prognoses and show less therapeutic efficacy towards immunotherapy and chemotherapy. Furthermore, we utilized a total of 36 pairs of tissue samples obtained from patients with CRC, along with two CRC cell lines for validation in vitro. This comprehensive approach further enhances the scientific validity and reliability of the identified subtypes and risk score in their ability to predict prognosis, response to immunotherapy, and response to chemotherapy among CRC patients. CONCLUSION: We first established robust prognostic subtypes based on chemokines and chemokine receptors, which could potentially serve as a novel biomarker for guiding individualized treatment in patients with CRC undergoing immunotherapy and chemotherapy.


Assuntos
Quimiocinas , Neoplasias Colorretais , Imunoterapia , Receptores de Quimiocinas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Imunoterapia/métodos , Prognóstico , Feminino , Masculino , Quimiocinas/metabolismo , Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Idoso , Regulação Neoplásica da Expressão Gênica , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos
7.
Nucl Med Biol ; 134-135: 108912, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691942

RESUMO

Chemokine receptors are important components of cellular signaling and play a critical role in directing leukocytes during inflammatory reactions. Their importance extends to numerous pathological processes, including tumor differentiation, angiogenesis, metastasis, and associations with multiple inflammatory disorders. The necessity to monitor the in vivo interactions of cellular chemokine receptors has been driven the recent development of novel positron emission tomography (PET) imaging agents. This imaging modality provides non-invasive localization and quantitation of these receptors that cannot be provided through blood or tissue-based assays. Herein, we provide a review of PET imaging of the chemokine receptors that have been imaged to date, namely CXCR3, CXCR4, CCR2, CCR5, and CMKLR1. The quantification of these receptors can aid in understanding various diseases, including cancer, atherosclerosis, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. The development of specific radiotracers targeting these receptors will be discussed, including promising results for disease diagnosis and management. However, challenges persist in fully translating these imaging advancements into practical therapeutic applications. Given the success of CXCR4 PET imaging to date, future research should focus on clinical translation of these approaches to understand their role in the management of a wide variety of diseases.


Assuntos
Tomografia por Emissão de Pósitrons , Receptores de Quimiocinas , Humanos , Tomografia por Emissão de Pósitrons/métodos , Animais , Receptores de Quimiocinas/metabolismo
8.
J Chem Inf Model ; 64(11): 4587-4600, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38809680

RESUMO

AlphaFold and AlphaFold-Multimer have become two essential tools for the modeling of unknown structures of proteins and protein complexes. In this work, we extensively benchmarked the quality of chemokine-chemokine receptor structures generated by AlphaFold-Multimer against experimentally determined structures. Our analysis considered both the global quality of the model, as well as key structural features for chemokine recognition. To study the effects of template and multiple sequence alignment parameters on the results, a new prediction pipeline called LIT-AlphaFold (https://github.com/LIT-CCM-lab/LIT-AlphaFold) was developed, allowing extensive input customization. AlphaFold-Multimer correctly predicted differences in chemokine binding orientation and accurately reproduced the unique binding orientation of the CXCL12-ACKR3 complex. Further, the predictions of the full receptor N-terminus provided insights into a putative chemokine recognition site 0.5. The accuracy of chemokine N-terminus binding mode prediction varied between complexes, but the confidence score permitted the distinguishing of residues that were very likely well positioned. Finally, we generated a high-confidence model of the unsolved CXCL12-CXCR4 complex, which agreed with experimental mutagenesis and cross-linking data.


Assuntos
Benchmarking , Quimiocinas , Modelos Moleculares , Conformação Proteica , Quimiocinas/metabolismo , Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/química , Ligação Proteica , Humanos , Sequência de Aminoácidos
9.
Int J Biol Macromol ; 268(Pt 1): 131679, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38641274

RESUMO

Over the past few decades, significant strides have been made in understanding the pivotal roles that chemokine networks play in tumor biology. These networks, comprising chemokines and their receptors, wield substantial influence over cancer immune regulation and therapeutic outcomes. As a result, targeting these chemokine systems has emerged as a promising avenue for cancer immunotherapy. However, therapies targeting chemokines face significant challenges in solid tumor treatment, due to the complex and fragile of the chemokine networks. A nuanced comprehension of the complicacy and functions of chemokine networks, and their impact on the tumor microenvironment, is essential for optimizing their therapeutic utility in oncology. This review elucidates the ways in which chemokine networks interact with cancer immunity and tumorigenesis. We particularly elaborate on recent innovations in manipulating these networks for cancer treatment. The review also highlights future challenges and explores potential biomaterial strategies for clinical applications.


Assuntos
Quimiocinas , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Quimiocinas/metabolismo , Animais , Imunoterapia/métodos , Portadores de Fármacos/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Receptores de Quimiocinas/metabolismo
10.
Dev Neurobiol ; 84(3): 128-141, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38616340

RESUMO

Adult neurogenesis continues throughout life but declines dramatically with age and in neurodegenerative disorders such as Alzheimer's disease. In parallel, microglia become activated resulting in chronic inflammation in the aged brain. A unique type of microglia, suggested to support neurogenesis, exists in the subventricular zone (SVZ), but little is known how they are affected by aging. We analyzed the transcriptome of aging microglia and identified a unique neuroprotective activation profile in aged SVZ microglia, which is partly shared with disease-associated microglia (DAM). CX3C motif chemokine receptor 1 (CX3CR1) is characteristically expressed by brain microglia where it directs migration to targets for phagocytosis. We show that Cx3cr1 expression, as in DAM, is downregulated in old SVZ microglia and that heterozygous Cx3cr1 mice have increased proliferation and neuroblast number in the aged SVZ but not in the dentate gyrus, identifying CX3CR1 signaling as a novel age and brain region-specific regulator of neurogenesis.


Assuntos
Envelhecimento , Receptor 1 de Quimiocina CX3C , Microglia , Neurogênese , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Neurogênese/fisiologia , Microglia/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Ativação Transcricional/fisiologia , Encéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética
11.
Tissue Cell ; 88: 102374, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38598873

RESUMO

The adipokines, visfatin, chemerin, and its receptor are expressed in the testis. It has also been shown that heat-stress alters the secretion and expression of other adipokines. Testicular heat-stress is now well known to cause the impairment in the testis. It has also been documented that heat-stress changes the expression of genes and proteins in the testis. To the best of our knowledge, the expression and localization of visfatin chemerin and its receptor have not been investigated in the heat-stressed testis. Therefore, the present study has investigated the expression and localization of these proteins in the heat-stressed testis. The expression of visfatin and chemerin and receptor exhibits a differential repossess against the heat stress. Visfatin expression was up-regulated while chemerin and chemerin receptor was down-regulated in the heat-stressed testis as shown by western blot analysis. The immunolocalization of visfatin and chemerin showed increased abundance in the seminiferous tubules of heat-stressed mice testis. Furthermore, abundance of visfatin, chemerin, and its receptor showed a decrease in abundance in the Leydig cells of heat-stressed testis. The decreased abundance of these proteins in the Leydig cells coincides with decreased 3ß-HSD immunostaining along with decreased testosterone levels. These results suggest that heat-stress might decrease testosterone secretion by modulating visfatin and chemerin in the Leydig cells. The increased abundance of visfatin and chemerin in the primary spermatocytes, round spermatid, and multinucleated germ cells also coincides with increased immunostaining of active caspase-3. Moreover, expression of Bcl-2 was down-regulated, and expression of active caspase-3 and HSP70 were up-regulated along with increased oxidative stress in the heat-stressed testis, suggesting stimulated apoptosis. In conclusion, our results showed that visfatin, chemerin, and its receptor are differentially expressed in the testis under heat-stress and within the testis also it might differentially regulate testosterone biosynthesis in the Leydig cells and apoptosis in the seminiferous tubules.


Assuntos
Quimiocinas , Resposta ao Choque Térmico , Nicotinamida Fosforribosiltransferase , Receptores de Quimiocinas , Testículo , Masculino , Animais , Camundongos , Quimiocinas/metabolismo , Testículo/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Células Intersticiais do Testículo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Caspase 3/metabolismo
12.
Dig Dis Sci ; 69(5): 1562-1570, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38580886

RESUMO

Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.


Assuntos
Quimiocinas , Neoplasias Esofágicas , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/imunologia , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Biomarcadores Tumorais/metabolismo , Prognóstico
13.
Medicine (Baltimore) ; 103(16): e37803, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640336

RESUMO

An increase in CD4+ T cells in the synovium is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify the possible causes of the elevated CD4+ T cell levels and to explore the factors influencing disease activity in RA. Fifty-five RA patients, including 28 with active RA (ARA), 27 with inactive RA, and 22 healthy controls, were recruited for this study. The proportion of CCR9+CD4+ T cells and the expression of chemokine receptor 9 (CCR9) on CD4+ T cells were analyzed by flow cytometry. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to evaluate interleukin (IL)-17A and IL-6 levels, respectively. The proportion of CCR9+CD4+ T cells and the expression of CCR9 on CD4+ T cells increased significantly in peripheral blood (PB) and synovial fluid (SF) in ARA compared to those in inactive RA. Furthermore, SF contained more CCR9+CD4+ T cells, IL-6, and IL-17A than PB in RA patients. Moreover, CD4+ T cells in the PB of patients with RA, especially ARA, expressed more CCR9 and secreted more IL-6 and IL-17A after activation. Here, we also demonstrated that both the percentage of CCR9+ cells in CD4+ T cells and the expression of CCR9 on circulating CD4+ T cells were positively correlated with erythrocyte sedimentation rate, hypersensitive C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide antibody. CCR9+CD4+ T cells are elevated in PB and SF, and are associated with disease activity in patients with RA.


Assuntos
Artrite Reumatoide , Linfócitos T CD4-Positivos , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Receptores de Quimiocinas/metabolismo , Líquido Sinovial
14.
PLoS Negl Trop Dis ; 18(4): e0012112, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38669292

RESUMO

Visceral leishmaniasis (VL) is a potentially fatal parasitic infection caused by Leishmania donovani in India. L. donovani is an obligate intracellular protozoan residing mostly in macrophages of the reticuloendothelial system throughout chronic infection. Monocytic phagocytes are critical in the pathogenesis of different forms of leishmaniasis. Subsets of monocytes are distinguished by their surface markers into CD14+CD16- classical monocytes, CD14+CD16+ intermediate monocytes, and CD16++CD14low non-classical monocyte subsets. During cutaneous leishmaniasis (CL), intermediate monocyte are reported to be a source of inflammatory cytokines IL-1ß and TNF, and they express CCR2 attracting them to sites of inflammatory pathology. We examined monocyte subsets in the blood and bone marrow of patients with VL from an endemic site in Bihar, India, and found these contrasted with the roles of monocytes in CL. During VL, intermediate and non-classical CD16+ monocyte subsets expressed instead a non-inflammatory phenotype with low CCR2, high CX3CR1 and low microbicidal oxidant generation, making them more similar to patrolling monocytes than inflammatory cells. Bone marrow CD16+ monocyte subsets expressed a phenotype that might be more similar to the inflammatory subsets of CL, although our inability to obtain bone marrow from healthy donors in the endemic region hampered this interpretation Overall the data suggest that CD16+ intermediate monocyte subsets in VL patients express a phenotypes that contributes to an immunosuppressed pathologic immune state, but in contrast to CL, these do not mediate localized inflammatory responses.


Assuntos
Medula Óssea , Leishmaniose Visceral , Monócitos , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Humanos , Monócitos/imunologia , Índia , Adulto , Masculino , Medula Óssea/parasitologia , Feminino , Receptores de IgG/análise , Receptores de IgG/metabolismo , Leishmania donovani/imunologia , Leishmania donovani/fisiologia , Adulto Jovem , Adolescente , Receptores CCR2/metabolismo , Pessoa de Meia-Idade , Criança , Receptores de Quimiocinas/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Citocinas/metabolismo
15.
Int Immunopharmacol ; 133: 112047, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38631221

RESUMO

BACKGROUND: Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are a limited number of reports regarding the clinical grading, prognostic impact, and utility of chemokines. Therefore, conducting a meta-analysis is necessary to obtain convincing and conclusive results. METHODS: A comprehensive literature search was conducted using various databases, including PubMed, Web of Science, The Cochrane Library, Embase, Ovid Medline, CNKI, Wanfang Database, VIP, and CBM. The search encompassed articles published from the inception of the databases until March 2024. The estimated odds ratio (ORs), standard mean difference (SMDs), and hazard ratio (HR) with their corresponding 95% confidence intervals (95% CI) were calculated to assess the predictive value of chemokine and receptor levels in glioma risk. Additionally, heterogeneity tests and bias tests were performed to evaluate the reliability of the findings. RESULTS: This meta-analysis included a total of 36 studies, involving 2,480 patients diagnosed with glioma. The results revealed a significant association between the expression levels of CXCR4 (n = 8; OR = 22.28; 95 % CI = 11.47-43.30; p = 0.000), CXCL12 (n = 4; OR = 10.69; 95 % CI = 7.03-16.24; p = 0.000), CCL2 (n = 6; SMD = -0.83; 95 % CI = -0.98--0.67; p = 0.000), CXCL8 (n = 3; SMD = 0.75; 95 % CI = 0.47-1.04; p = 0.000), CXCR7 (n = 3; OR = 20.66; 95 % CI = 10.20-41.82; p = 0.000), CXCL10 (n = 2; SMD = 3.27; 95 % CI = 2.91-3.62; p = 0.000) and the risk of glioma. Additionally, a significant correlation was observed between CXCR4 (n = 8; OR = 4.39; 95 % CI = 3.04-6.32; p = 0.000), (n = 6; SMD = 1.37; 95 % CI = 1.09-1.65; p = 0.000), CXCL12 (n = 6; OR = 6.30; 95 % CI = 3.87-10.25; p = 0.000), (n = 5; ES = 2.25; 95 % CI = 1.15-3.34; p = 0.041), CCL2 (n = 3; OR = 9.65; 95 % CI = 4.55-20.45; p = 0.000), (n = 4; SMD = -1.47; 95 % CI = -1.68--1.26; p = 0.000), and CCL18 (n = 3; SMD = 1.62; 95 % CI = 1.30-1.93; p = 0.000) expression levels and high-grade glioma (grades 3-4). Furthermore, CXCR4 (HR = 2.38, 95 % CI = 1.66-3.40; p = 0.000) exhibited a strong correlation with poor overall survival (OS) rates in glioma patients. CONCLUSION: The findings of this study showed a robust association between elevated levels of CXCR4, CXCL12, CCL2, CXCL8, CXCL10 and CXCR7 with a higher risk of glioma. Furthermore, the WHO grading system was validated by the strong correlation shown between higher expression of CXCR4, CXCL12, CCL2, and CCL18 and WHO high-grade gliomas (grades 3-4). Furthermore, the results of the meta-analysis suggested that CXCR4 might be a helpful biomarker for predicting the worse prognosis of glioma patients.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Glioma/mortalidade , Glioma/imunologia , Glioma/metabolismo , Prognóstico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/imunologia , Biomarcadores Tumorais/metabolismo , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores CXCR4/metabolismo
16.
Int J Mol Sci ; 25(8)2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38673909

RESUMO

Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid ß (Aß). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aß plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aß deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1-/-). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aß plaques in APP/PS1-Cmklr1-/- mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aß42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aß42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aß plaques/Aß42.


Assuntos
Doença de Alzheimer , Astrócitos , Quimiocinas , Peptídeos e Proteínas de Sinalização Intercelular , Placa Amiloide , Receptores de Quimiocinas , Animais , Astrócitos/metabolismo , Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Humanos , Peptídeos beta-Amiloides/metabolismo , Camundongos Knockout , Movimento Celular , Transdução de Sinais , Camundongos Transgênicos , Camundongos Endogâmicos C57BL
17.
Infect Immun ; 92(5): e0000624, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38629806

RESUMO

Enterococci are common commensal bacteria that colonize the gastrointestinal tracts of most mammals, including humans. Importantly, these bacteria are one of the leading causes of nosocomial infections. This study examined the role of colonic macrophages in facilitating Enterococcus faecalis infections in mice. We determined that depletion of colonic phagocytes resulted in the reduction of E. faecalis dissemination to the gut-draining mesenteric lymph nodes. Furthermore, we established that trafficking of monocyte-derived CX3CR1-expressing macrophages contributed to E. faecalis dissemination in a manner that was not reliant on CCR7, the conventional receptor involved in lymphatic migration. Finally, we showed that E. faecalis mutants with impaired intracellular survival exhibited reduced dissemination, suggesting that E. faecalis can exploit host immune cell migration to disseminate systemically and cause disease. Our findings indicate that modulation of macrophage trafficking in the context of antibiotic therapy could serve as a novel approach for preventing or treating opportunistic infections by disseminating enteric pathobionts like E. faecalis.


Assuntos
Receptor 1 de Quimiocina CX3C , Colo , Enterococcus faecalis , Macrófagos , Receptores CCR2 , Receptores de Quimiocinas , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Macrófagos/microbiologia , Macrófagos/imunologia , Camundongos , Colo/microbiologia , Colo/imunologia , Receptores CCR2/metabolismo , Receptores CCR2/genética , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Infecções por Bactérias Gram-Positivas/imunologia , Infecções por Bactérias Gram-Positivas/microbiologia , Camundongos Endogâmicos C57BL , Linfonodos/microbiologia , Linfonodos/imunologia , Receptores CCR7/metabolismo , Receptores CCR7/genética
18.
Reprod Toxicol ; 126: 108599, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38679149

RESUMO

OBJECTIVE: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant difficulties in social interaction, communication, and repeated stereotypic behaviour. Aflatoxin B1 (AFB1) is the most potent and well-known mycotoxin in various food sources. Despite its propensity to generate significant biochemical and structural changes in human and animal tissues, the influence of AFB1 on ASD has yet to be thoroughly studied. Mounting evidence indicates that chemokine receptors play a crucial function in the central nervous system and are implicated in developing several neuroinflammatory disorders. Chemokine receptors in individuals with ASD were elevated in the anterior cingulate gyrus astrocytes, cerebellum, and brain. METHODS: The BTBR T+Itpr3tf/J (BTBR) mice are inbred strains that exhibit strong and consistently observed deficits in social interactions, characterized by excessive self-grooming and limited vocalization in social contexts. We examined the impact of AFB1 on CCR3-, CCR7-, CCR9-, CXCR3-, CXCR4-, and CXCR6-expressing I-A/I-E+ cells in the spleen of the BTBR mouse model of autism. We evaluated the mRNA levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 chemokine receptors in the brain. RESULTS: The exposure to AFB1 in BTBR mice resulted in a significant rise in the number of I-A/I-E+CCR3+, I-A/I-E+CCR7+, I-A/I-E+CCR9+, I-A/I-E+CXCR3+, I-A/I-E+CXCR4+, and I-A/I-E+CXCR6+ cells. Furthermore, exposure to AFB1 increased mRNA expression levels of CCR3, CCR7, CCR9, CXCR3, CXCR4, and CXCR6 in the brain. CONCLUSIONS: These findings highlight that AFB1 exposure increases the expression of chemokine receptors in BTBR mice, indicating the necessity for further research into AFB1's role in the development of ASD.


Assuntos
Aflatoxina B1 , Transtorno do Espectro Autista , Encéfalo , Modelos Animais de Doenças , Baço , Animais , Transtorno do Espectro Autista/induzido quimicamente , Aflatoxina B1/toxicidade , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Masculino , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Camundongos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo
19.
Cells ; 13(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38474365

RESUMO

Obesity is associated with low-grade chronic inflammation and impaired glucose metabolism, both of which are detrimental to wound healing. C-C motif chemokine receptor 2 (CCR2) plays an important role in cell recruitment during healing, and our recent studies revealed the significance of CCR2-CCL2 signaling in promoting the proliferation of pro-inflammatory monocytes/macrophages in wounds. Therefore, we sought to determine whether diet-induced obesity increases monocyte/macrophage proliferation and their accumulation in skin wounds. We first confirmed that wound closure was delayed in obese CCR2RFP/+ mice fed with a high-fat diet (HFD) compared to mice fed with a normal diet (ND). Using in vivo imaging and flow cytometry analysis, we found that HFD mice had significantly increased accumulation of CCR2+ monocytes/macrophages, particularly pro-inflammatory CCR2+Ly6C+ cells in wounds compared to their ND counterparts. Importantly, HFD mice exhibited an increased proliferation of wound CCR2+Ly6C+ compared to ND mice. Together, our data suggest that obesity leads to an increased proliferation and accumulation of pro-inflammatory CCR2+Ly6C+ monocytes/macrophages in skin wounds, which may contribute to delayed healing.


Assuntos
Macrófagos , Monócitos , Camundongos , Animais , Monócitos/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Dieta Hiperlipídica , Receptores de Quimiocinas/metabolismo , Cicatrização , Proliferação de Células
20.
Cell Mol Immunol ; 21(6): 533-545, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38532043

RESUMO

The skin is the most common site of Staphylococcus aureus infection, which can lead to various diseases, including invasive and life-threatening infections, through evasion of host defense. However, little is known about the host factors that facilitate the innate immune evasion of S. aureus in the skin. Chemerin, which is abundantly expressed in the skin and can be activated by proteases derived from S. aureus, has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1. Here, we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S. aureus in a mouse model of cutaneous infection, whereas chemerin overexpression, which mimics high levels of chemerin in obese individuals, exacerbates S. aureus cutaneous infection. Mechanistically, we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S. aureus-induced IL-33 expression, leading to impaired skin neutrophilia and bacterial clearance. CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S. aureus by inhibiting Akt activation in mouse keratinocytes. Thus, our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S. aureus in vivo and likely increases susceptibility to S. aureus infection in obese individuals.


Assuntos
Quimiocinas , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular , Queratinócitos , Receptores de Quimiocinas , Staphylococcus aureus , Animais , Queratinócitos/imunologia , Queratinócitos/metabolismo , Staphylococcus aureus/imunologia , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Camundongos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Endogâmicos C57BL , Humanos , Transdução de Sinais , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/patologia , Infecções Estafilocócicas/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pele/imunologia , Pele/patologia , Pele/microbiologia , Camundongos Knockout
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