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1.
Cell Mol Life Sci ; 81(1): 296, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992165

RESUMO

Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.


Assuntos
Antígenos de Diferenciação de Linfócitos B , Linfócitos T CD4-Positivos , COVID-19 , Antígenos de Histocompatibilidade Classe II , Oxirredutases Intramoleculares , Ativação Linfocitária , Fatores Inibidores da Migração de Macrófagos , SARS-CoV-2 , Humanos , Antígenos de Diferenciação de Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Ativação Linfocitária/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Movimento Celular , Masculino , Feminino , Pessoa de Meia-Idade , Receptores Imunológicos
2.
Mult Scler Relat Disord ; 88: 105716, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38880030

RESUMO

BACKGROUND: Chronic fatigue is one of the most common, disabling, and least understood symptoms of many chronic health conditions including multiple sclerosis (MS). A multidisciplinary rehabilitative treatment approach is recommended for MS-related fatigue, but few people with MS have access to such treatment. In-person and telehealth cognitive behavioral therapy (CBT) for fatigue is an emerging acceptable and effective treatment for MS-related fatigue in civilians that has not been studied in Veterans with MS, a population that is more likely to be older, male, unemployed, and disabled. The present study aimed to understand how Veterans with MS (1) describe their fatigue and (2) manage their fatigue, and (3) perceive telehealth CBT for MS-related fatigue. METHOD: Twenty-four Veterans with MS completed semi-structured interviews and a brief survey. For descriptive purposes, the survey included questionnaires on demographics, fatigue, psychosocial functioning, depression, and pain. Thematic analysis with a combined deductive and inductive approach was used to analyze interview transcripts. RESULTS: Three themes emerged. First, "experience of MS fatigue as 'one big tapestry'" described fatigue as deficits in physical and mental energy that were fluctuating and complex in their interaction with biological factors. Veterans described that MS fatigue negatively impacted daily activities of living, emotions, and cognitive functioning. Second, "managing MS fatigue through trial and error" revealed that Veterans expend significant time and effort learning and trialing fatigue management strategies based on their personal beliefs, military training/experiences, provider recommendations, and iterative learning. Most Veterans described energy management, relaxation, exercise, and adaptive thinking as helpful for managing fatigue. Interestingly, the helpfulness of medication for fatigue was highly variable, and none of the Veterans described medication as a standalone fatigue treatment. The third theme, "practicing flexibility with telehealth CBT for MS fatigue" revealed Veteran's enthusiasm about telehealth CBT for MS-related fatigue and highlighted the importance of flexible delivery to meet individual needs. CONCLUSION: Veteran participants shared their experience of MS-related fatigue as well as management strategies that are consistent with previous research in civilians with MS fatigue. Notably, Veterans' preference for flexible nonpharmacological intervention can inform adaptation of telehealth CBT for Veterans with MS fatigue.

3.
Int J Mol Sci ; 24(22)2023 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-38003252

RESUMO

The interaction between integrin α4ß7 and mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) facilitates the adhesion of circulating lymphocytes to the surface of high endothelial venules in inflammatory bowel diseases (IBDs). Lymphocyte adhesion is a multistep cascade involving the tethering, rolling, stable adhesion, crawling, and migration of cells, with integrin α4ß7 being involved in rolling and stable adhesions. Targeting the integrin α4ß7-MAdCAM-1 interaction may help decrease inflammation in IBDs. This interaction is regulated by force; however, the underlying mechanism remains unknown. Here, we investigate this mechanism using a parallel plate flow chamber and atomic force microscopy. The results reveal an initial increase in the lifetime of the integrin α4ß7-MAdCAM-1 interaction followed by a decrease with an increasing force. This was manifested in a two-state curve regulated via a catch-bond-slip-bond conversion regardless of Ca2+ and/or Mg2+ availability. In contrast, the mean rolling velocity of cells initially decreased and then increased with the increasing force, indicating the flow-enhanced adhesion. Longer tether lifetimes of single bonds and lower rolling velocities mediated by multiple bonds were observed in the presence of Mg2+ rather than Ca2+. Similar results were obtained when examining the adhesion to substrates co-coated with chemokine CC motif ligand 25 and MAdCAM-1, as opposed to substrates coated with MAdCAM-1 alone. In conclusion, the integrin α4ß7-MAdCAM-1 interaction occurs via ion- and cytokine-dependent flow-enhanced adhesion processes and is regulated via a catch-bond mechanism.


Assuntos
Imunoglobulinas , Integrinas , Adesão Celular , Imunoglobulinas/química , Linfócitos
4.
OTJR (Thorofare N J) ; 43(3): 457-466, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36912395

RESUMO

BACKGROUND: Skills to manage the chronic effect of stroke are often not sufficiently addressed in early stroke rehabilitation. OBJECTIVES: The study evaluated the feasibility of conducting a trial testing the efficacy of telehealth self-management support early in stroke recovery. METHODOLOGY: Process, resources, and scientific feasibility was assessed for a randomized controlled trial comparing the effect of motivational interviewing and a group-based self-management program to treatment-as-usual with first-time stroke patients. Data were analyzed using descriptive statistics, effect sizes, and thematic analysis. RESULTS: Fifteen stroke patients were enrolled, and 10 completed the study (intervention n = 6). 100% attendance was achieved with technical support, reminders, and schedule flexibility. Participants were satisfied with the intervention and reported emotional benefits and gain of new insights. Perceived recovery showed moderate effect (r = 0.54). CONCLUSION: The findings support the feasibility of an efficacy trial as well as the potential benefit of integrating telehealth self-management support early in stroke rehabilitation.


Assuntos
Autogestão , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Telemedicina , Humanos , Estudos de Viabilidade , Acidente Vascular Cerebral/psicologia
5.
FASEB J ; 37(3): e22752, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36794636

RESUMO

Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age-dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe-/- mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. Mif-deficient mice exhibited reduced atherosclerotic lesions in the 30/24- and 42/36-week-old groups, but atheroprotection, which in the applied Apoe-/- model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42- and 52/6-week-old groups. This suggested that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age-related phenotypes. We found that Mif deficiency promotes lesional macrophage and T-cell counts in younger but not aged mice, with subgroup analysis pointing toward a role for Trem2+ macrophages. The transcriptomic analysis identified pronounced MIF- and aging-dependent changes in pathways predominantly related to lipid synthesis and metabolism, lipid storage, and brown fat cell differentiation, as well as immunity, and atherosclerosis-relevant enriched genes such as Plin1, Ldlr, Cpne7, or Il34, hinting toward effects on lesional lipids, foamy macrophages, and immune cells. Moreover, Mif-deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm'aging are either not downregulated or even upregulated in Mif-deficient aged mice compared with the corresponding younger ones. Lastly, Mif deficiency favored formation of lymphocyte-rich peri-adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif-gene deficiency in atherogenic Apoe-/- mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm'aging and MIF pathways in atherosclerosis and may have implications for translational MIF-directed strategies.


Assuntos
Aterosclerose , Fatores Inibidores da Migração de Macrófagos , Placa Aterosclerótica , Animais , Camundongos , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Aterosclerose/metabolismo , Quimiocinas , Envelhecimento , Apolipoproteínas E/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Glicoproteínas de Membrana , Receptores Imunológicos
6.
FASEB J ; 36(11): e22601, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36269019

RESUMO

Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF.


Assuntos
Doenças Cardiovasculares , Inflamação , Oxirredutases Intramoleculares , Humanos , Quimiocinas/metabolismo , Inflamação/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo
7.
J Cell Biochem ; 120(8): 14165-14174, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30963639

RESUMO

Prostate cancer (PCa) is the third most common reason of cancer-related deaths in men. Accumulating evidence has shown that dysregulation of long noncoding RNAs (lncRNAs) is closely related to cancer initiation and development. Although large numbers of lncRNAs have been discovered, knowledge regarding their function and physiological/pathological significance remains limited. In this study, we aimed to reveal functional lncRNAs and identify prognosis-related RNAs in PCa by analyzing data from The Cancer Genome Atlas (TCGA). To achieve this, an lncRNA-mRNA coexpression network was constructed by weighted correlation network analysis. Additionally, a subnetwork was extracted from this weighted correlation network, and seven lncRNAs were identified as core nodes. Further Kaplan-Meier survival analysis showed that three lncRNAs (LINC00683, LINC00857, and FENDRR) were significantly downregulated in PCa samples, and there was a strong positive correlation with patient survival. Importantly, LINC00683 has not been fully reported as related with PCa. Additionally, gene set enrichment analysis indicated that LINC00683 might be involved in cancer-related pathways such as the Wnt pathway. Based on the findings of this study, lncRNA LINC00683 is likely to provide a new diagnostic biomarker and therapeutic target for future PCa treatments.


Assuntos
Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Humanos , Masculino , Prognóstico , Mapas de Interação de Proteínas/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Gênica , Regulação para Cima/genética , Via de Sinalização Wnt/genética
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