Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

Liu, Yudong; Gibson, Sara A.; Benveniste, Etty N.; Qin, Hongwei

doi:10.1615/critrevimmunol.2016015517

Cited by 28 publications

(20 citation statements)

References 179 publications

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“…In this study, we have investigated the IL-6/STAT3-, IL-12/STAT4-, and IL-23/STAT3-pathways in MS and the contribution of the genetic background to the responsiveness of these pathways. Earlier studies have indicated JAK/STAT-pathways as a potential therapeutic target in MS [21,22], and our finding of a donor-specific increased activity of the IL-12- and IL-23-induced STAT-pathways strengthens the perception that certain individuals may benefit from treatment. Previously, a phase II study tested the efficacy of a neutralizing antibody against the p40 subunit of IL-12 and IL-23 (ustekinumab), with the intention to block IL-12 and IL-23 signaling pathways in patients with RRMS.…”

Section: Discussionsupporting

confidence: 80%

IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

Essen

Søndergaard

Petersen

et al. 2019

Cells

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Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.

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Section: Discussionsupporting

confidence: 80%

IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

Essen

Søndergaard

Petersen

et al. 2019

Cells

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“…Dysregulation of the JAK-STAT pathway resulted in autoimmune diseases, such as MS/EAE. Currently, many studies focus on the therapeutic targets of this pathway [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis

Luo

2018

Oncotarget

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Multiple sclerosis is a chronic autoimmune disorder of the central nervous system. In MS, the genetic susceptibility is high and currently there is no effective treatment. MicroRNA, a small non-coding RNA, plays a vital role in immune responses. Aberrant or dysfunctional miRNAs may cause several diseases, including MS, thus miRNAs and miRNA related genes may be therapeutic weapons against MS. Here, we identified 21 miRNAs in peripheral blood mono-nuclear cells from over 600 persons, including healthy controls. By using informatics databases, 1637 susceptibility genes were evaluated and Cytoscape was used to integrate and visualize the relation between the miRNA identified and susceptibility genes. By using the cluster Profile package, a total of 10 risk pathways were discovered. Top pathways included: hsa05200 (pathway in cancer), hsa04010 (MAPK signaling pathway), and hsa04060 (cytokine-cytokine receptor interaction). By using the STRING database, a protein-protein interaction network was conducted to identify highly susceptibility genes. Moreover, the GSE21942 dataset was used to indicate the gene expression profiles and to correct prediction results, thereby identifying the most pivotal genes. The MiRSystem database provided information on both pivotal miRNAs and genes. In conclusion, miR-199a and miR-142-3p may be crucial for MS by targeting pivotal susceptibility genes, in particular KRAS and IL7R.

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“…By contrast, STAT3 ablation worsens neuroinflammation in mice with spinal cord injury ( 56 ), and STAT3 activation alleviates cuprizone-induced CNS demyelination ( 57 ). This discordancy may depend on spatiotemporally specific activation of STAT3 ( 58 ). Indeed, in contrast to macrophages, IL-19 deficiency did not affect activation of DCs.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation

et al. 2021

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Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

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Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

Cited by 28 publications

References 179 publications

IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis

Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation

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