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C-X-C motif chemokine receptor 4 (CXCR4)-directed molecular imaging provides excellent read-out capabilities in patients with marginal zone lymphoma (MZL). We aimed to determine the interobserver agreement rate of CXCR4-targeted PET/CT among readers with different levels of experience. METHODS: 50 subjects with MZL underwent CXCR4-targeted PET/CT, which were reviewed by four readers (including two experienced and two less experienced observers). The following 8 parameters were investigated: overall scan result, CXCR4 density in lymphoma tissue, extranodal organ involvement, No. of affected extranodal organs and extranodal organ metastases, lymph node (LN) involvement and No. of affected LN areas and LN metastases. We applied intraclass correlation coefficients (ICC; < 0.4, poor; 0.4-0.59, fair; 0.6-0.74, good and > 0.74 excellent agreement rates). RESULTS: Among all readers, fair agreement was recorded for No. of affected extranodal organs (ICC, 0.40; 95% confidence interval [CI], 0.25-0.68), overall scan result (ICC, 0.42; 95%CI, 0.28-0.57), CXCR4 density in lymphoma tissue (ICC, 0.52; 95%CI, 0.38-0.66), and No. of extranodal organ metastases (ICC, 0.55; 95%CI, 0.41-0.61) and LN involvement (ICC, 0.59; 95%CI, 0.46-0.71). Good agreement rates were observed for No. of LN metastases (ICC, 0.71; 95%CI, 0.60-0.81) and No. of LN areas (ICC, 0.73; 95%CI, 0.63-0.82), while extranodal organ involvement (ICC, 0.35; 95%CI, 0.21-0.51) achieved poor concordance. On a reader-by-reader comparison, the experienced readers achieved significantly higher agreement rates in 4/8 (50%) investigated scan items (ICC, range, 0.21-0.90, P < / = 0.04). In the remaining 4/8 (50%), a similar trend with higher ICCs for the experienced readers was recorded (n.s.). CONCLUSION: CXCR4-directed PET/CT mainly provided fair to good agreement rates for scan assessment, while a relevant level of experience seems to be required for an accurate imaging read-out.
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BACKGROUND: The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. METHODS: We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3-/- and Cxcl10-/-) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3-/- and Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3-/-or Cxcl10-/- recipient mice (CD45.2) and examined donor-contributed hematopoiesis. RESULTS: Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10-/- donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. CONCLUSIONS: The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.
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Diferenciação Celular , Quimiocina CXCL10 , Células-Tronco Hematopoéticas , Receptores CXCR3 , Animais , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Camundongos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Autorrenovação Celular , Hematopoese , Transplante de Células-Tronco HematopoéticasRESUMO
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 4B and C on p. 1952, and the Transwell invasion assay data in Fig. 2F and 4I, had already appeared in previously published articles written by different authors at different research institutes (a number of which have been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 42: 19461956, 2019; DOI: 10.3892/or.2019.7302].
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CC chemokine receptor 2 and CCL2 are highly involved in cancer growth and metastasis, and immune escape. Raised sodium ion concentrations in solid tumours have also been correlated to metastasis and immune modulation. Sodium ions can modulate class A G protein-coupled receptors through the sodium ion binding site characterized by a highly conserved aspartic acid residue (D2.50), also present in CCR2. Hence, we further explored this binding site in CCR2 by radioligand binding studies and mutagenesis. Modulation of three distinctly binding radioligands by sodium ions and amiloride derivates was investigated. Sodium ions were observed to be relatively weak modulators of antagonist binding, but substantially increased 125I-CCL2 dissociation from CCR2. 6-Substituted Hexamethylene Amiloride (HMA) modulated all tested radioligands. Induced-fit docking of HMA in the presumed sodium ion binding site of CCR2 confirmed its binding site. Finally, investigation of (cancer-associated) mutations in the sodium ion binding site showed a markedly decreased expression compared to wild type. Only two mutants, G123A3.35 and G127K3.39, were able to be bound by [3H]INCB3344 and [3H]CCR2-RA-[R]. Thus, mutagenesis showed that the sodium ion binding site residues, which are distinct from other class A GPCRs and related to chemokine receptor evolution, are crucial for receptor integrity. Moreover, the tested mutations appeared to have no effect on modulation observed by HMA or a minor effect on sodium chloride modulation on the tested radioligands. All in all, these results invite further exploration of the CCR2 sodium ion binding site in (cancer) biology, and potentially as a third druggable binding site.
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Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression.
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Toxoplasma gondii (T. gongii) is a zoonotic protozoan parasite that causes congenital toxoplasmosis, including fetal death, abortion, stillbirth, morphological abnormalities, and premature birth. Primary T. gondii infection in pregnant women results in congenital toxoplasmosis. C-C chemokine receptor (CCR) 2 is reportedly a critical host defense factor against T. gondii infection. However, details of the role of CCR2 in the host immune response to T. gondii in congenital toxoplasmosis remain unclear. Here, we infected pregnant CCR2-deficient mice with T. gondii, resulting in stillbirth, embryonic resorption, fetal morphological abnormalities, and preterm delivery at significantly higher rates than those in pregnant wild-type mice. Consistent with the severity of abnormal pregnancy, a large area of placental hemorrhage and a large number of T. gondii infections around the hemorrhagic area were observed in the placentas of CCR2-deficient mice. In addition, the accumulation of inflammatory monocytes in the placenta was reduced in CCR2-deficient mice during infection. We further confirmed that the adoptive transfer of inflammatory monocytes collected from wild-type mice into T. gondii-infected pregnant CCR2-deficient mice effectively suppressed placental damage and abnormal pregnancy. Collectively, CCR2 contributes to pregnancy maintenance by regulating the migration of inflammatory monocytes into the placenta of T. gondii-infected pregnant mice.
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Chemokines regulate leukocyte navigation to inflamed sites and specific tissue locales and may therefore be useful for ensuring accurate homing of cell therapeutic products. We, and others, have shown that atypical chemokine receptor 2 (ACKR2), deficient mice (ACKR2-/-) are protected from metastasis development in cell line and spontaneous mouse models. We have shown that this relates to enhanced CCR2 expression on ACKR2-/- NK cells allowing them to home more effectively to CCR2 ligand expressing metastatic deposits. Here we demonstrate that the metastatic-suppression phenotype in ACKR2-/- mice is not a direct effect of the absence of ACKR2. Instead, enhanced NK cell CCR2 expression is caused by passenger-mutations that originate from creation of the ACKR2-/- mouse strain in 129 embryonic stem cells. We further demonstrate that simple selection of CCR2+ NK cells enriches for a population of cells with enhanced anti-metastatic capabilities. Given the widespread expression of CCR2 ligands by tumors, our study highlights CCR2 as a potentially important contributor to NK cell tumoricidal cell therapy.
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The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C-C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. METHODS: This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. RESULTS: Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. CONCLUSIONS: The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.
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Quimiocina CCL2 , Macrófagos , Camundongos Knockout , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Doença Pulmonar Obstrutiva Crônica , Receptores CCR2 , Transdução de Sinais , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Receptores CCR2/metabolismo , Receptores CCR2/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Humanos , Camundongos Endogâmicos C57BL , MasculinoRESUMO
Introduction: In coronavirus disease 2019 (COVID-19), particularly in older people, dysregulated immune response and aberrant repair can result in varied severity secondary pulmonary fibrosis (PF). By detecting some indicators, the occurrence and prognosis of fibrosis can be measured, providing directions for COVID-19 treatment. Methods: The research study lasted for 3 months and involved 88 COVID-19 patients. According to the chest radiological examination, 47 (53.41%) individuals were found to have no PF, while 41 (46.59%) showed PF. Clinical data such as inflammation markers, imaging findings, blood gas analysis, and hospital stay length were collected. Results: With area under the curve values of 0.7413, 0.7741, and 0.7048, respectively, and the study of the receiver operating characteristic curve demonstrated that mucin 1 (MUC1), carcinoembryonic antigen (CEA), and CXC chemokine receptor 10 (CXCL10) could diagnose the presence of COVID-19 PF. To evaluate the possibility of PF following severe acute respiratory syndrome coronavirus-2 infection, we established particular values for MUC1, CEA, and CXCL10 (1.296 ng/ml, 4.315 ng/ml, and 32.77 ng/ml, respectively). The survival curve for hospital days indicated that the length of hospital stays positively correlated with these three factors (P < 0.01). Transforming growth factor-beta did not correlate significantly with the severity of COVID-19 or PF. Conclusion: The results of this study suggested that the MUC1, CEA, and CXCL10 can be employed to explore the severity of secondary PF in COVID-19.
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C-X-C motif chemokine receptor 4 (CXCR4) is a promising therapeutic target of breast cancer because it is overexpressed on cell surface of all molecular subtypes of breast cancer including triplenegative breast cancer (TNBC). Herein, CXCR4 antagonistic peptide-NaGdF4 nanodot conjugates (termed as anti-CXCR4-NaGdF4 NDs) have been constructed for magnetic resonance imaging (MRI)-guided biotherapy of TNBC through conjugation of the C-X-C Motif Chemokine 12 (CXCL12)-derived cyclic peptide with tryptone coated NaGdF4 nanodots (5 ± 0.5 nm in diameter, termed as Try-NaGdF4 NDs). The as-prepared anti-CXCR4-NaGdF4 NDs exhibits high longitudinal relaxivity (r1) value (21.87 mM-1S-1), reasonable biocompatibility and good tumor accumulation ability. The features of anti-CXCR4-NaGdF4 NDs improve the tumor-MRI sensitivity and facilitate tumor biotherapy after injection in mouse-bearing MDA-MB-231 tumor model in vivo. MRI-guided biotherapy using anti-CXCR4-NaGdF4 NDs enables to suppress 46% tumor growth. In addition, about 47% injection dose of anti-CXCR4-NaGdF4 NDs is found in the mouse urine at 24 h post-injection. These findings demonstrate that anti-CXCR4-NaGdF4 NDs enable to be used as renal clearable nanomedicine for biotherapy and MRI of breast cancer.
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Neoplasias da Mama , Imageamento por Ressonância Magnética , Receptores CXCR4 , Receptores CXCR4/metabolismo , Animais , Feminino , Imageamento por Ressonância Magnética/métodos , Humanos , Camundongos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Gadolínio/química , Quimiocina CXCL12/metabolismo , Camundongos Nus , Camundongos Endogâmicos BALB C , Nanopartículas/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Peptídeos/químicaRESUMO
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the certain of the cell proliferation assay data shown in Fig. 4C on p. 1444 were strikingly similar to data appearing in different form in another article written by different authors at different research institutes, which had already been submitted for publication [Shi N, Shan B, Song Y, Chu H and Qian L: Circular RNA circPRKCI functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR36803p in esophageal squamous cell carcinoma. J Cell Biochem 120: 1002110030, 2019]. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 21: 14391448, 2020; DOI: 10.3892/mmr.2020.10957].
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Multiple myeloma (MM) is a plasma cell disease with a preferential bone marrow (BM) tropism. Enforced expression of tissue-specific chemokine receptors has been shown to successfully guide adoptively-transferred CAR NK cells towards the malignant milieu in solid cancers, but also to BM-resident AML and MM. For redirection towards BM-associated chemokine CXCL12, we armored BCMA CAR-NK-92 as well as primary NK cells with ectopic expression of either wildtype CXCR4 or a gain-of-function mutant CXCR4R334X. Our data showed that BCMA CAR-NK-92 and -primary NK cells equipped with CXCR4 gained an improved ability to migrate towards CXCL12 in vitro. Beyond its classical role coordinating chemotaxis, CXCR4 has been shown to participate in T cell co-stimulation, which prompted us to examine the functionality of CXCR4-cotransduced BCMA-CAR NK cells. Ectopic CXCR4 expression enhanced the cytotoxic capacity of BCMA CAR-NK cells, as evidenced by the ability to eliminate BCMA-expressing target cell lines and primary MM cells in vitro and through accelerated cytolytic granule release. We show that CXCR4 co-modification prolonged BCMA CAR surface deposition, augmented ZAP-70 recruitment following CAR-engagement, and accelerated distal signal transduction kinetics. BCMA CAR sensitivity towards antigen was enhanced by virtue of an enhanced ZAP-70 recruitment to the immunological synapse, revealing an increased propensity of CARs to become triggered upon CXCR4 overexpression. Unexpectedly, co-stimulation via CXCR4 occurred in the absence of CXCL12 ligand-stimulation. Collectively, our findings imply that co-modification of CAR-NK cells with tissue-relevant chemokine receptors affect adoptive NK cell therapy beyond improved trafficking and retention within tumor sites.
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Antígeno de Maturação de Linfócitos B , Quimiocina CXCL12 , Imunoterapia Adotiva , Células Matadoras Naturais , Mieloma Múltiplo , Receptores CXCR4 , Receptores de Antígenos Quiméricos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Humanos , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/metabolismo , Antígeno de Maturação de Linfócitos B/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Quimiocina CXCL12/metabolismo , Linhagem Celular Tumoral , Citotoxicidade ImunológicaRESUMO
Regulatory T cells (Tregs) are known to facilitate tumor progression by suppressing CD8+ T cells within the tumor microenvironment (TME), thereby also hampering the effectiveness of immune checkpoint inhibitors (ICIs). While systemic depletion of Tregs can enhance antitumor immunity, it also triggers undesirable autoimmune responses. Therefore, there is a need for therapeutic agents that selectively target Tregs within the TME without affecting systemic Tregs. In this study, as shown also by others, the chemokine (C-C motif) receptor 8 (CCR8) was found to be predominantly expressed on Tregs within the TME of both humans and mice, representing a unique target for selective depletion of tumor-residing Tregs. Based on this, we developed BAY 3375968, a novel anti-human CCR8 antibody, along with respective surrogate anti-mouse CCR8 antibodies, and demonstrated their in vitro mode-of-action through induction of potent antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities. In vivo, anti-mouse CCR8 antibodies effectively depleted Tregs within the TME primarily via ADCP, leading to increased CD8+ T cell infiltration and subsequent tumor growth inhibition across various cancer models. This monotherapeutic efficacy was significantly enhanced in combination with ICIs. Collectively, these findings suggest that CCR8 targeting represents a promising strategy for Treg depletion in cancer therapies. BAY 3375968 is currently under investigation in a Phase I clinical trial (NCT05537740).
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Receptores CCR8 , Linfócitos T Reguladores , Microambiente Tumoral , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Receptores CCR8/imunologia , Receptores CCR8/antagonistas & inibidores , Animais , Camundongos , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Feminino , Citotoxicidade Celular Dependente de Anticorpos , Depleção Linfocítica , Linhagem Celular Tumoral , Fagocitose/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêuticoRESUMO
Chemokines regulate the trophoblast dysfunction involved in the occurrence and development of pathological pregnancy, including missed abortions. In particular, CXC chemokine receptor type 5 mediates cell proliferation, migration, and inflammation; nonetheless, its role in missed abortions remains unclear. This study aimed to examine the expression of CXC chemokine receptor type 5 in missed abortions and to investigate the effects of CXC chemokine receptor type 5 on the biological behaviour of trophoblasts, as well as the underlying mechanisms. Our results indicated that CXC chemokine receptor type 5 was upregulated in the villi of women who experienced unexplained missed abortions, as compared with those who had normal pregnancies. CXC chemokine receptor type 5 inhibited the proliferation and migration of human first-trimester trophoblast/simian virus cells but promoted cell apoptosis. With respect to its mechanisms, CXC chemokine receptor type 5 activated the extracellular signal-regulated protein kinase 1/2 signalling pathway and upregulated the secretion of interleukin-6; however, it had no effect on the secretion of tumour necrosis factor-α. In conclusion, our findings suggest that CXC chemokine receptor type 5 induces trophoblast dysfunction and participates in the processes of unexplained missed abortions, wherein p-ERK and interleukin-6 may be involved.
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Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
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Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31 weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and ≥ 70 years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.
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Anticorpos Monoclonais Humanizados , Linfoma Cutâneo de Células T , Linfoma de Células T Periférico , Receptores CCR4 , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Receptores CCR4/antagonistas & inibidores , Adulto , Japão , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Idoso de 80 Anos ou mais , Vigilância de Produtos Comercializados , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto Jovem , Resistencia a Medicamentos AntineoplásicosRESUMO
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease with abnormal differentiation of follicular helper T (Tfh) cells, Total alkaloids of Sophora alopecuroides Linn. (Leguminosae) (TASA) have potential effects on collagen-induced arthritis (CIA) mice, while the mechanism needs further elucidation. The purpose of this study is to explore the regulation of TASA on rheumatoid arthritis and related mechanism. Methods: The proportion of Tfh and B lymphocytes in peripheral blood lymphocytes of RA patients was examined by flow cytometry. We constructed the collagen induced arthritis DBA/1J mice model. Between days 15 and 45 following the first immunization, the mice were treated intraperitoneally with saline, TASA (100, 50, and 25 mg/kg), and dexamethasone (DXM) for 30 days. Molecular biological techniques such as FCM, PCR, ELISA, and Western-blotting were used to examine Tfh cells and associated signal pathways. Results: Our results indicated that the follicular helper T cells and B lymphocytes in rheumatoid arthritis patients were significantly increased compared with the healthy control. The percentage of Tfh cells are correlated with RA related inflammatory factors. Total alkaloids of Sophora alopecuroides Linn. could significantly attenuate joint swelling. Meanwhile, it reduced the frequencies of spleen Tfh, B lymphocytes and the expression of TLR2, TLR9, p-NF-κBp65, CXCR5, Bcl-6, ICOS of ankle joints in CIA mice. Conclusion: Total alkaloids of Sophora alopecuroides Linn. may down-regulate the frequency and function of Tfh cells and inhibit GCB cells via TLRs/NF-κB signal pathway to relieve the immune-pathological progression of CIA mice.
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Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the clinical effects and underlying mechanisms of washed microbiota transplantation (WMT), a refined method of fecal microbiota transplantation, for the treatment of MAFLD remain unclear. In this study, both patients and mice with MAFLD exhibit an altered gut microbiota composition. WMT increases the levels of beneficial bacteria, decreases the abundance of pathogenic bacteria, and reduces hepatic steatosis in MAFLD-affected patients and mice. Downregulation of the liver-homing chemokine receptor CXCR6 on ILC3s results in an atypical distribution of ILC3s in patients and mice with MAFLD, characterized by a significant reduction in ILC3s in the liver and an increase in ILC3s outside the liver. Moreover, disease severity is negatively correlated with the proportion of hepatic ILC3s. These hepatic ILC3s demonstrate a mitigating effect on hepatic steatosis through the release of IL-22. Mechanistically, WMT upregulates CXCR6 expression on ILC3s, thereby facilitating their migration to the liver of MAFLD mice via the CXCL16/CXCR6 axis, ultimately contributing to the amelioration of MAFLD. Overall, these findings highlight that WMT and targeting of liver-homing ILC3s could be promising strategies for the treatment of MAFLD.
Assuntos
Quimiocina CXCL16 , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Fígado , Receptores CXCR6 , Animais , Receptores CXCR6/metabolismo , Quimiocina CXCL16/metabolismo , Camundongos , Humanos , Fígado/metabolismo , Fígado/microbiologia , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Imunidade Inata , Fígado Gorduroso/terapia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/microbiologia , Interleucina 22 , Hepatopatia Gordurosa não Alcoólica/terapia , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Interleucinas/metabolismo , FemininoRESUMO
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.