<p>Targeting Chemokines and Chemokine Receptors in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis</p>

Journal of Inflammation Research, Год журнала: 2020, Номер Volume 13, С. 619 - 633

Опубликована: Сен. 1, 2020

Abstract: Multiple sclerosis (MS) is an immune-mediated and neurodegenerative disorder that results in inflammation demyelination of the central nervous system (CNS). MS symptoms include walking difficulties, visual weakening, as well learning memory impairment, thus affecting quality patient's life. Chemokines chemokine receptors are expressed on immune cells CNS resident cells. Several sets their ligands tend to be pathogenic players MS, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL17, CCL19, CCL21, CCL22, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL16. Furthermore, current modulatory drugs used treatment its animal model, experimental autoimmune encephalomyelitis (EAE), affect expression several receptors. In this review, we highlight roles chemokines utilizing them potential therapeutic targets through selective agents, such specific antibodies receptor blockers, or indirectly EAE immunomodulatory drugs. Keywords: multiple sclerosis, encephalomyelitis, chemokines,

Язык: Английский

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COVID-19 and Rheumatoid Arthritis Crosstalk: Emerging Association, Therapeutic Options and Challenges

Cells, Год журнала: 2021, Номер 10(12), С. 3291 - 3291

Опубликована: Ноя. 24, 2021

Hyperactivation of immune responses resulting in excessive release pro-inflammatory mediators alveoli/lung structures is the principal pathological feature coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). The cytokine hyperactivation COVID-19 appears to be similar those seen rheumatoid arthritis (RA), an autoimmune disease. Emerging evidence conferred severity and risk RA patients. Amid musculoskeletal manifestations involving immune-inflammation-dependent mechanisms cases arthralgia and/or myalgia COVID-19, crosstalk between often debated. present article sheds light on RA, patients acquiring SARS-CoV-2 infection, aspects infection development. We also whether can exacerbate outcomes based available clinical readouts. mechanistic overlapping immune-inflammatory features both was discussed. showed emerging links angiotensin-converting enzyme (ACE)-dependent macrophage-mediated pathways diseases. Moreover, a detailed review immediate challenges key recommendations for anti-rheumatic drugs setting presented better monitoring management Taken together, summarizes knowledge their overlaps, challenges, therapeutic options.

Язык: Английский

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Recapitulating monocyte extravasation to the synovium in an organotypic microfluidic model of the articular joint

Biofabrication, Год журнала: 2021, Номер 13(4), С. 045001 - 045001

Опубликована: Июнь 17, 2021

Abstract The synovium of osteoarthritis (OA) patients can be characterized by an abnormal accumulation macrophages originating from extravasated monocytes. Since targeting monocyte extravasation may represent a promising therapeutic strategy, our aim was to develop organotypic microfluidic model recapitulating this process. Synovium and cartilage were modeled hydrogel-embedded OA synovial fibroblasts articular chondrocytes separated fluid channel. compartment included perfusable endothelialized channel dedicated injection. Monocyte in response chemokines quantified. efficacy chemokine receptor antagonists, RS-504393 (CCR2 antagonist) Cenicriviroc (CCR2/CCR5 inhibiting tested pre-incubating monocytes with the antagonists before After designing fabricating chip, culture conditions optimized achieve including fibroblasts, chondrocytes, continuous endothelial monolayer expressing intercellular adhesion molecule-1 vascular cell molecule-1. A significantly higher number mix ( p < 0.01) 0.01), compared control condition. In both cases, endothelium pre-activation enhanced extravasation. simultaneous blocking CCR2 CCR5 proved more effective 0.001) than only 0.01). study provided direct evidence that induces cross invade compartment. exploited either test molecules antagonizing process or investigate effect on cells.

Язык: Английский

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CCL21/CCR7 axis as a therapeutic target for autoimmune diseases

International Immunopharmacology, Год журнала: 2023, Номер 121, С. 110431 - 110431

Опубликована: Июнь 16, 2023

Язык: Английский

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CXCL13 promotes TNF-α synthesis in rheumatoid arthritis through activating ERK/p38 pathway and inhibiting miR-330-3p generation

Biochemical Pharmacology, Год журнала: 2024, Номер 221, С. 116037 - 116037

Опубликована: Фев. 1, 2024

Язык: Английский

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Upregulation of interferon-γ response genes in monocytes and T cells identified by single-cell transcriptomics in patients with anti-citrullinated peptide antibody-positive early rheumatoid arthritis

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 14, 2025

Introduction Our aim was to investigate the insufficiently understood differences in immune system between anti-citrullinated peptide antibody (ACPA)-positive (ACPA + ) and ACPA-negative - early rheumatoid arthritis (eRA) patients. Methods We performed multiple cytokine assays using sera from drug-naïve ACPA eRA Additionally, we conducted single-cell RNA sequencing of CD45 cells peripheral blood samples analyze compare distribution functional characteristics cell subsets based on status. Results Serum concentrations interferon-γ (IFN-γ) interleukin (IL)-12 were higher than eRA. Single-cell transcriptome analysis 37,318 identified 17 distinct types revealed expansion IL1B proinflammatory monocytes, IL7R T cells, CD8 CCL4 Furthermore, observed an enrichment IFN-γ response genes nearly all monocytes subsets. Heightened interactions receptors eRA, particularly cells. examined IFITM2 IFITM3 as potential key markers given their pronounced upregulation association with IFN response. Specifically, expression these elevated (likely M1 monocytes), correlating serum levels. Discussion Compared showed IL-12 levels, upregulated genes, enhanced IFN-γ-driven monocyte-T interactions. These features circulation suggest a role for type 1 helper cell-related immunity its pathogenesis.

Язык: Английский

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Exploring new drug treatment targets for immune related bone diseases using a multi omics joint analysis strategy

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 27, 2025

Язык: Английский

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Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases

Drug Discovery Today, Год журнала: 2020, Номер 26(4), С. 1030 - 1039

Опубликована: Дек. 30, 2020

Inflammatory diseases are believed to develop as a result of dysregulated inflammatory responses environmental factors on susceptible genetic backgrounds. Operating at the level post-transcriptional gene regulation, miRNAs class endogenous, small noncoding RNAs that can promote downregulation protein expression by translational repression and/or mRNA degradation target mRNAs involved in inflammation. MiR-124 is crucial modulator inflammation and innate immunity could provide therapeutic restitution physiological pathways lost diseases. A recently discovered quinoline, ABX464, was shown upregulate miR-124 human immune cells. In vivo, proof-of-concept clinical study, ABX464 showed robust consistent efficacy ulcerative colitis (UC). this review, we examine current options proposed for UC discuss drug candidate context.

Язык: Английский

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Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Дек. 13, 2021

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune adaptive responses has come into view. Under homeostatic conditions, short-lived continuously released from bone marrow. Their development starts undifferentiated hematopoietic stem pass through different immature subtypes eventually become fully equipped, mature capable launching fast robust responses. During severe (systemic) inflammation, there is an increased need neutrophils. The rapidly adapts this demand by switching steady-state blood cell production emergency granulopoiesis. granulopoiesis, de novo marrow at extramedullary sites augmented, while additional marginated pools. Although indispensable host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation neutrophil homeostasis imperative. In review, we discuss kinetics ontogenesis conditions during myelopoiesis provide overview molecular players involved regulation. We substantiate review example autoinflammatory disease, i.e. systemic juvenile idiopathic arthritis.

Язык: Английский

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Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study

Annals of the Rheumatic Diseases, Год журнала: 2022, Номер 81(8), С. 1076 - 1084

Опубликована: Май 31, 2022

Objective This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg 100 per day), which upregulates biogenesis mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) 60 patients (1:1:1 ratio) moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and an anti-tumour necrosis factor alpha (TNFα) therapy. Methods The primary end point was ABX464; endpoints included proportion achieving American College Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified score, clinical score), European League Against Rheumatism response, DAS28 low or remission. Results safe well tolerated. Two serious adverse events were reported (one on one mg). Eleven withdrawn for AEs (9 mg, 1 placebo). Drug discontinuation mainly due gastrointestinal disorders. No cases opportunistic infection, no malignancies death reported. Compared placebo, showed significantly higher proportions ACR20 ACR50 responses at week 12. DAS28-C reactive protein (CRP) DAS28-erythrocyte sedimentation rate decreased rates categorical DAS28-CRP CDAI remission increased A significant upregulation miR-124 observed blood every patient dosed ABX464. Conclusion safe, tolerated promising efficacy. Mild-to-moderate led high drop-out may not be relevant dose use. These findings warrant exploration day less treating RA. Trial registration name Phase IIa group, multiple MTX, moderate severe RA anti- TNFα therapy intolerance anti-TNFα EUDRACT number: 2018-004677-27 number NCT03813199 .

Язык: Английский

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