• Immunosuppression
• M‐MDSCs
• Periprosthetic joint infection
• Staphylococcus aureus
• Treg

• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• Animals
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Mice
• Receptors, CXCR6/metabolism
• Receptors, CXCR6/genetics
• Biofilms
• Humans
• Transforming Growth Factor beta/metabolism
• Chemokine CXCL16/metabolism
• Chemokine CXCL16/genetics
• Staphylococcus aureus/immunology
• Staphylococcal Infections/immunology
• Staphylococcal Infections/metabolism
• Disease Models, Animal
• Female
• Male
• Prosthesis-Related Infections/immunology
• Prosthesis-Related Infections/metabolism
• Prosthesis-Related Infections/microbiology
• Middle Aged

• 82372424 National Natural Science Foundation of China
• 82203677 National Natural Science Foundation of China
• GZC20233275 Postdoctoral Fellowship Program of CPSF
• 82302716 Young Scientists Fund of the National Natural Science Foundation of China
• 2024M753776 China Postdoctoral Science Foundation
• 2023M744048 China Postdoctoral Science Foundation
• 2023A1515140147 Basic and Applied Basic Research Foundation of Guangdong Province
• National Natural Science Foundation of China
• China Postdoctoral Science Foundation
• Basic and Applied Basic Research Foundation of Guangdong Province

• 17594 Shiraz University of Medical Sciences
• Shiraz University of Medical Sciences

• rheumatoid arthritis
• joints
• bone
• therapeutics
• biologicals
• drugs
• jaks
• noncoding rnas

• cytokine release syndrome
• humans
• matrix metalloproteinases
• mucocutaneous lymph node syndrome
• single-cell gene expression analysis

• Child
• Humans
• Infant
• Mucocutaneous Lymph Node Syndrome/complications
• Mucocutaneous Lymph Node Syndrome/diagnosis
• Mucocutaneous Lymph Node Syndrome/genetics
• Leukocytes, Mononuclear
• Coronary Vessels/pathology
• Cross-Sectional Studies
• Transcriptome
• Tumor Necrosis Factor-alpha
• Coronary Artery Disease/genetics
• Coronary Artery Disease/complications

• Autoimmune diseases
• Autoimmune hepatitis
• CXCL16
• CXCR6
• Iinflammatory bowel diseases
• Multiple sclerosis
• Psoriasis
• Rheumatoid arthritis

• Bcl-2
• CXCL-16
• Double-blind placebo-controlled clinical trial
• KOOS
• Metformin
• Osteoarthritis
• Polymorphism
• mTOR

• Humans
• Quality of Life
• Proto-Oncogene Proteins c-bcl-2
• Osteoarthritis, Knee/drug therapy
• Osteoarthritis, Knee/genetics
• Metformin/therapeutic use
• Genetic Variation
• Chemokine CXCL16

• Shiraz University of Medical Sciences

• Adult-onset Still’s disease
• CXCR3
• Chemokine
• Juvenile idiopathic arthritis
• Rheumatoid arthritis
• Spondyloarthritis

• Humans
• Arthritis
• Autoimmune Diseases
• CD8-Positive T-Lymphocytes
• Ligands
• Receptors, CXCR3/genetics
• Interferons/pharmacology

• C16/17/010 Onderzoeksraad, KU Leuven
• 11L3122N FWO-Vlaanderen
• G067123N FWO Vlaanderen

• Humans
• Arthritis, Rheumatoid/metabolism
• Joints/pathology
• Autoantibodies
• Autoimmunity
• Mesenchymal Stem Cells/metabolism

• B cell aggregates
• CSF
• Chemokines
• EAE
• MP4

• calcium signal
• inflammation
• inflammatory pain
• neuro-inflammation
• rheumatoid arthritis
• transient receptor potential channels

• blockade
• chemokine
• chemokine receptor
• leukocyte
• migration
• rheumatoid arthritis

• Tumor microenvironment
• chemokines
• prognostic markers
• therapeutics

• tumour immunology
• autoimmunity

• Arthritis/chemically induced
• Arthritis/drug therapy
• CD8-Positive T-Lymphocytes
• Humans
• Immune Checkpoint Inhibitors/adverse effects
• Immunotherapy/adverse effects
• Neoplasms/drug therapy
• Neoplasms/etiology

• P30 CA016672 NCI NIH HHS
• K01 AI163412 NIAID NIH HHS
• R01 HL141966 NHLBI NIH HHS
• R01 CA284684 NCI NIH HHS
• S10 OD024977 NIH HHS
• R01 AI083761 NIAID NIH HHS
• P50 CA221703 NCI NIH HHS
• R01 HL143520 NHLBI NIH HHS
• P50 CA070907 NCI NIH HHS
• K08 AR079587 NIAMS NIH HHS
• Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)

• Cytokines
• Glucose
• Humans
• Inflammation/drug therapy
• Injections, Intra-Articular
• Osteoarthritis, Knee/drug therapy
• Prolotherapy/methods
• Treatment Outcome

• Animals
• Cell- and Tissue-Based Therapy
• Immunotherapy, Adoptive
• Mesothelin
• Mice
• Pancreatic Neoplasms/therapy
• Receptors, CXCR6/metabolism
• Receptors, Chemokine/genetics
• T-Lymphocytes

• R01 AI123349 NIAID NIH HHS
• 866411 European Research Council
• R00 CA215604 NCI NIH HHS
• P01 CA240239 NCI NIH HHS
• 756017 European Research Council

• epigenetic regulators
• proteins
• rheumatoid arthritis
• small molecular metabolites
• targets

• RA
• T cells
• macrophage
• pathogenesis
• targeted therapy

• Animals
• Arthritis, Rheumatoid/etiology
• Arthritis, Rheumatoid/metabolism
• Arthritis, Rheumatoid/pathology
• Biomarkers
• Cell Communication/immunology
• Disease Susceptibility
• Humans
• Immunomodulation
• Macrophages/immunology
• Macrophages/metabolism
• Synovial Membrane/pathology
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism

• CD8-positive T-lymphocytes
• adaptive immunity
• immunization
• vaccination

• Administration, Intranasal
• Animals
• CD8-Positive T-Lymphocytes/drug effects
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Cancer Vaccines/administration & dosage
• Cancer Vaccines/immunology
• Cancer Vaccines/pharmacology
• Cell Line, Tumor
• Chemokine CXCL16/metabolism
• Female
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/immunology
• Head and Neck Neoplasms/metabolism
• Humans
• Immunologic Memory
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/immunology
• Lung Neoplasms/metabolism
• Lymphocytes, Tumor-Infiltrating/drug effects
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Memory T Cells/drug effects
• Memory T Cells/immunology
• Memory T Cells/metabolism
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Receptors, CXCR6/deficiency
• Receptors, CXCR6/genetics
• Tumor Burden/drug effects
• Tumor Microenvironment
• Vaccination
• Vaccine Efficacy
• Mice

• Fondation ARC pour la Recherche sur le Cancer
• H2020 European Research Council
• Institut National Du Cancer

Individuals carrying anti-citrullinated protein antibodies (ACPA) are considered at high risk of developing rheumatoid arthritis (RA). The altered expression of miRNAs contributes to the pathogenesis of RA. We aimed to identify differentially expressed miRNAs in the peripheral blood of ACPA-positive individuals with arthralgia at risk of RA compared to healthy controls (HC) and to determine their implications in the preclinical phase of RA. A comprehensive analysis of miRNAs revealed the dysregulation of miR-451 in peripheral blood mononuclear cells (PBMC) and plasma from RA-risk individuals. Higher miR-451 expression in PBMC from RA-risk individuals was further validated. Notably, miR-451 was previously shown to regulate CXCL16, a protein involved in RA pathogenesis. The expression of miR-451 in PBMC positively correlated with the CXCL16 mRNA, which could be secondary to the inflammation-induced expression of miR-451. Transfection of monocytes with pre-miR-451 in vitro resulted in the downregulation of CXCL16. Moreover, flow cytometry revealed a lower count of CXCL16-positive monocytes in RA-risk individuals. We propose that the constitutive or inflammation-induced upregulation of miR-451 in PBMC downregulates the expression of CXCL16, reduces the inflammatory milieu and thereby strives to delay the shift from the preclinical phase to the clinical manifestation of RA. This hypothesis warrants further investigation.

The balance between the responsiveness of the intestinal immune system and the gut environment is fundamental for the maintenance of intestinal homeostasis, which is required for an adequate recognition of entering antigens. The disruption of this homeostasis by exaggerated immune response to harmless antigens can lead to the development of intestinal disorders such as inflammatory bowel disease. Stromal cells are sessile non-hematopoietic cells that build the backbone of the lymph node, an important site for the immune response induction, but also contribute to immune response and tolerance induction. However, the knowledge about the role of stromal cells in the regulation of inflammatory responses is still limited. Therefore, in this study we analyzed the influence of stromal cells on the development of chronic intestinal inflammation. Here, we show that intestinal inflammation alters the immune activation of the mesenteric lymph node-derived stromal cells. Podoplanin⁺ and CD21/35⁺ stromal cells showed increased expression of MHC class II molecules, but CD106 expression on CD21/35⁺ cells was reduced. Stromal cells secreted cytokines and chemokines such as CCL7 and CXCL16 influenced the gut-homing phenotype and proliferation of CD4⁺ and CD8⁺ T cells. Furthermore, stromal cells of peripheral lymph nodes transplanted into the mesentery attenuated colitis severity in B6-Il10^-/- mice. The reduced colitis severity in these mice was associated with increased expression of IL4 and distinct activation pattern of stromal cells derived from transplanted peripheral lymph nodes. Altogether, our results demonstrate that lymph node stromal cells impact development of chronic colitis via T cell induction. Moreover, lymph node stromal cells from different draining area due to neonatally imprinted processes distinctly regulate the induction of immune responses.

• chemokine
• cytokines
• lymph nodes
• stromal cells
• transplantation

The transmembrane chemokine pathways CXCL16/CXCR6 and CX3CL1/CX3CR1 are strongly implicated in inflammation and angiogenesis. We investigated the involvement of these chemokine pathways and their processing metalloproteinases ADAM10 and ADAM17 in the pathophysiology of proliferative diabetic retinopathy (PDR). Vitreous samples from 32 PDR and 24 non-diabetic patients, epiretinal membranes from 18 patients with PDR, rat retinas, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by enzyme-linked immunosorbent assay, immunohistochemistry and Western blot analysis. In vitro angiogenesis assays were performed and the adherence of leukocytes to CXCL16-stimulated HRMECs was assessed. CXCL16, CX3CL1, ADAM10, ADAM17 and vascular endothelial growth factor (VEGF) levels were significantly increased in vitreous samples from PDR patients. The levels of CXCL16 were 417-fold higher than those of CX3CL1 in PDR vitreous samples. Significant positive correlations were found between the levels of VEGF and the levels of CXCL16, CX3CL1, ADAM10 and ADAM17. Significant positive correlations were detected between the numbers of blood vessels expressing CD31, reflecting the angiogenic activity of PDR epiretinal membranes, and the numbers of blood vessels and stromal cells expressing CXCL16, CXCR6, ADAM10 and ADAM17. CXCL16 induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB and VEGF in cultured Müller cells and tumor necrosis factor-α induced upregulation of soluble CXCL16 and ADAM17 in Müller cells. Treatment of HRMECs with CXCL16 resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and increased leukocyte adhesion to HRMECs. CXCL16 induced HRMEC proliferation, formation of sprouts from HRMEC spheroids and phosphorylation of ERK1/2. Intravitreal administration of CXCL16 in normal rats induced significant upregulation of the p65 subunit of NF-κB, VEGF and ICAM-1 in the retina. Our findings suggest that the chemokine axis CXCL16/CXCR6 and the processing metalloproteinases ADAM10 and ADAM17 might serve a role in the initiation and progression of PDR.

• ADAM10
• ADAM17
• CX3CL1
• CXCL16
• chemokines
• metalloproteinases
• proliferative diabetic retinopathy

• MSU crystals
• gouty arthritis
• migration
• mucosal-associated invariant T cells
• osteoclastogenesis

Arrest of circulating leukocytes and subsequent diapedesis is a fundamental component of inflammation. In general, the leukocyte migration cascade is tightly regulated by chemoattractants, such as chemokines. Chemokines, small secreted chemotactic cytokines, as well as their G-protein-coupled seven transmembrane spanning receptors, control the migratory patterns, positioning and cellular interactions of immune cells. Increased levels of chemokines and their receptors are found in the blood and within inflamed tissue in patients with rheumatoid arthritis (RA) and vasculitis. Chemokine ligand-receptor interactions regulate the recruitment of leukocytes into tissue, thus contributing in important ways to the pathogenesis of RA and vasculitis. Despite the fact that blockade of chemokines and chemokine receptors in animal models have yielded promising results, human clinical trials in RA using inhibitors of chemokines and their receptors have generally failed to show clinical benefits. However, recent early phase clinical trials suggest that strategies blocking specific chemokines may have clinical benefits in RA, demonstrating that the chemokine system remains a promising therapeutic target for rheumatic diseases, such as RA and vasuculitis and requires further study.

• Chemokine
• Rheumatoid arthritis
• Vasculitis

• CXCL16
• IL-1beta
• NK cells
• biomarker
• rheumatoid arthritis

• Adult
• Arthritis, Rheumatoid/blood
• Arthritis, Rheumatoid/diagnosis
• Arthritis, Rheumatoid/genetics
• Arthritis, Rheumatoid/pathology
• Biomarkers/blood
• Chemokine CXCL16/genetics
• Female
• Gene Expression Regulation/genetics
• Humans
• Interferon-gamma/genetics
• Interleukin-1beta/genetics
• Killer Cells, Natural/metabolism
• Killer Cells, Natural/pathology
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/pathology
• Male
• Middle Aged
• Tumor Necrosis Factor-alpha/genetics

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases and a prototypic inflammatory disease, affecting the small joints of the hands and feet. Chemokines and chemokine receptors play a critical role in RA pathogenesis via immune cells recruitment. Several chemokines and chemokine receptors are abundant in the peripheral blood and in the local inflamed joints of RA. Furthermore, synthetic and biologics disease modifying anti rheumatic drugs have been reported to affect chemokines expression. Thus, many studies have focused on targeting chemokines and chemokine receptors, where some have shown positive promising results. However, most of the chemokine blockers in human trials of RA treatment displayed some failures that can be attributed to several reasons in their structures and binding affinities. Nevertheless, targeting chemokines will continue to be under development, in order to improve their therapeutic potentials in RA and other autoimmune diseases. In this review we provide an up-to-date knowledge regarding the role of chemokines and chemokine receptors in RA with an emphasis on their activities on immune cells. We also discussed the effects of drugs targeting those molecules in RA. This knowledge might provide impetus for developing new therapeutic modalities to treat this chronic disease.

• chemokine receptors
• chemokines
• drugs
• immunotargets
• immunotherapy
• rheumatoid arthritis

Genetic associations imply a role for CD8+ T cells and the interleukin‐23 (IL‐23)/IL‐17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL‐17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL‐17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis.

Peripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6–18), T cell receptor β (TCRβ) sequencing (n = 3), RNA‐Seq (n = 3), quantitative reverse transcriptase–polymerase chain reaction (n = 4), and Luminex or enzyme‐linked immunosorbent assay (n = 4–16).

IL‐17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA‐Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue‐resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint.

Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

• Biomarker
• CXCL16/CXCR6
• Fibroblasts
• Interstitial lung disease

• gene module
• long non-coding RNA
• microRNA
• protein‒protein interaction network

• Adult
• Aged
• Arthritis, Rheumatoid/genetics
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation/genetics
• Gene Regulatory Networks
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• RNA, Long Noncoding/blood
• RNA, Long Noncoding/genetics

• CXCR6
• Fatty liver
• Hepatic NKT cells
• Ischemia-reperfusion injury

Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).

• CD4+ T cells
• T-cell subsets
• cytotoxic
• effector function
• helper
• rheumatoid arthritis
• tissue-resident

• chemokine
• cytotoxicity
• migration
• mucosal-associated cancer
• mucosal-associated invariant T cells

• Imbalance
• Primary immune thrombocytopenia
• Th1/Th2
• sCXCL16

• Endothelial cells
• Rheumatoid arthritis
• Synovial angiogenesis
• Vasculogenesis

• Preeclampsia
• alzheimer’s disease
• gene expression regulation
• inflammation
• oxidative stress
• placenta

• Animals
• Chemokines/metabolism
• Humans
• Lupus Erythematosus, Systemic/metabolism
• Lupus Erythematosus, Systemic/pathology
• Lupus Nephritis/metabolism
• Lupus Nephritis/pathology
• Receptors, Chemokine/metabolism

• R03 AI117597 NIAID NIH HHS