The Interplay Between Monocytes/Macrophages and CD4+ T Cell Subsets in Rheumatoid Arthritis

Roberts, Ceri A.; Dickinson, Abigail K.; Taams, Leonie S.

doi:10.3389/fimmu.2015.00571

Cited by 179 publications

(157 citation statements)

References 235 publications

(329 reference statements)

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“…Our results flag innate cell populations as alternative or additional contributors. Effects in Th cells were modest, but the reduction in numbers and expression of activation clusters in MFs was suggestive, in light of their integrative role in destructive synovitis (27). Conversely, perturbations of NK cells, in numbers or in the wiring of their effector networks, support the notion that NK deficits underlie, at least in part, the viral reactivation events [noting that no correlation between changes in proportions of blood NK cells and infectious adverse events in patients has been observed (10, 28)].…”

Section: Discussionmentioning

confidence: 95%

Network pharmacology of JAK inhibitors

Moodley

Yoshida

Mostafavi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Small-molecule inhibitors of the Janus kinase family (JAKis) are clinically efficacious in multiple autoimmune diseases, albeit with increased risk of certain infections. Their precise mechanism of action is unclear, with JAKs being signaling hubs for several cytokines. We assessed the in vivo impact of pan-and isoform-specific JAKi in mice by immunologic and genomic profiling. Effects were broad across the immunogenomic network, with overlap between inhibitors. Natural killer (NK) cell and macrophage homeostasis were most immediately perturbed, with network-level analysis revealing a rewiring of coregulated modules of NK cell transcripts. The repression of IFN signature genes after repeated JAKi treatment continued even after drug clearance, with persistent changes in chromatin accessibility and phospho-STAT responsiveness to IFN. Thus, clinical use and future development of JAKi might need to balance effects on immunological networks, rather than expect that JAKis affect a particular cytokine response and be cued to long-lasting epigenomic modifications rather than by short-term pharmacokinetics.JAK inhibitor | tofacitinib | systems pharmacology A drug's mechanism of action usually refers to the specific molecular or biologic activity that it perturbs, and drug optimization aims at maximizing potency and specificity vs. this target. However, the molecular target may be far removed from the processes that ultimately drive the therapeutic effect. For instance, even though the target is known, it remains unclear which cell or pathway is pivotally affected by anti-PD1 during cancer immunotherapy. Given the interdependencies of cellular and molecular players in biological systems, a drug is likely to have effects far broader than its molecular target. Conversely, it may be hampered by inherent resistance to perturbation of interconnected networks. This complexity is encapsulated in the concepts of network pharmacology, which proposes that drug development focus on network-level alterations, rather than on exquisite specificity for an individual target (1).JAK kinase inhibitors (JAKis) have been intensively and successfully pursued over the last two decades (2, 3) and could be considered poster children of network pharmacology. JAK kinases (JAK1/2/3 and TYK2) are the initial mediators of signaling pathways triggered by many cytokines and hematopoietic growth factors, and activate transducers of the STAT family to prompt cell activation and phenotypic differentiation in all immunocyte lineages (4). The cytokine network is an unusually interconnected one, because cytokines can induce each other, or each other's receptors, and can enhance or stifle each other's signaling pathways. Further complexity stems from the widespread sharing of JAK kinases by cytokine receptors (e.g., JAK1 is connected to receptors for interferons,

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Section: Discussionmentioning

confidence: 95%

Network pharmacology of JAK inhibitors

Moodley

Yoshida

Mostafavi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This results in increased secretion of proinflammatory mediators such as ROS/RNS, eicosanoids, cytokines (IL-17, TNF-a, interferon-g, IL-6, and IL-1b), and catabolic enzymes that trigger hyperproliferation of synovial fibroblasts, joint swelling, and progressive destruction of cartilage and bone (Roberts et al, 2015). Deletion of the NRF2 gene increases vulnerability to joint alterations in experimental RA models.…”

Section: B Nuclear Factor (Erythroid-derived 2)-like 2 In Autoimmunementioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…On the one hand, human peripheral blood monocytes are shown to act as antigen-processing cells (APCs) to activate T cells and secrete cytokines that shape T-cell differentiation in inflammatory diseases, such as rheumatoid arthritis and thrombocytopenia (23, 24). On the other hand, monocytes, which are generally regarded as precursors of tissue macrophages and dendritic cells (DCs) (25), can functionally promote B-cell differentiation and antibody secretion in patients with SLE (26, 27).…”

Section: Introductionmentioning

confidence: 99%

CD16+ Monocyte Subset Was Enriched and Functionally Exacerbated in Driving T-Cell Activation and B-Cell Response in Systemic Lupus Erythematosus

Zhu

Sun

et al. 2016

Front. Immunol.

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BackgroundThe roles that CD16+ monocyte subset plays in T-cell activation and B-cell response have not been well studied in systemic lupus erythematosus (SLE).ObjectiveThe present study aimed to investigate the distribution of CD16+ monocyte subsets in SLE and explore their possible roles in T-cell activation and B-cell differentiation.MethodsThe frequencies of monocyte subsets in the peripheral blood of healthy controls (HCs) and patients with SLE were determined by flow cytometry. Monocyte subsets were sorted and cocultured with CD4+ T cells and CD19+ B cells. Then, T and B cells were collected for different subset detection, while the supernatants were collected for immunoglobulin G, IgA, and IgM or interferon-γ and interleukin-17A detection by enzyme-linked immunosorbent assay.ResultsOur results showed that CD16+ monocytes exhibited a proinflammatory phenotype with elevated CD80, CD86, HLA-DR, and CX3CR1 expression on the cell surface. It’s further demonstrated that CD16+ monocytes from patients and HCs shared different cell-surface marker profiles. The CD16+ subset was enriched in SLE and had an exacerbated capacity to promote CD4+ T cell polarization into a Th17 phenotype. Also, CD16+ monocytes had enhanced impacts on CD19+ B cells to differentiate into plasma B cells and regulatory B cells with more Ig production.ConclusionThis study demonstrated that CD16+ monocytes, characterized by different cell-surface marker profiles, were enriched and played a critical role in driving the pathogenic T- and B-cell responses in patients with SLE.

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The Interplay Between Monocytes/Macrophages and CD4+ T Cell Subsets in Rheumatoid Arthritis

Cited by 179 publications

References 235 publications

Network pharmacology of JAK inhibitors

Network pharmacology of JAK inhibitors

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

CD16+ Monocyte Subset Was Enriched and Functionally Exacerbated in Driving T-Cell Activation and B-Cell Response in Systemic Lupus Erythematosus

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