Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers

Ferrandi, Chiara; Richard, Fabien; Tavano, Patrizia; Hauben, Ehud; Barbié, Valerie; Gotteland, Jean Pierre; Greco, Béatrice; Fortunato, Mara; Mariani, Maurizio; Furlan, Roberto; Comi, Giancarlo; Martino, Gianvito; Zaratin, Paola

doi:10.1177/1352458510381258

Cited by 35 publications

(27 citation statements)

References 47 publications

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“…There are currently no commercially available JNK inhibitors, but a few oral JNK inhibitors, including CC‐930 (tanzisertib) and AS602801 (bentamapimod), recently entered clinical trials. CC‐930 is being tested in idiopathic pulmonary fibrosis and high‐dose CC‐930 caused elevation of hepatic transaminases when used for long‐term treatment .…”

Section: Discussionmentioning

confidence: 99%

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is a life‐threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c‐Jun N‐terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+;Kras G12D/+ mice with JNK1 −/− mice to generate Ptf1a Cre/+ ;Kras G12D/+ ;JNK1 −/− (Kras;JNK1−/−) mice. Tumor weight was significantly lower in Kras;JNK1−/− mice than in Kras;JNK1+/− mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 −/− mice. Tumor diameters were significantly smaller in JNK1 −/− mice. Phosphorylated JNK (p‐JNK) was activated in α‐smooth muscle actin (SMA)‐positive cells in tumor stroma, and mPC‐conditioned medium activated p‐JNK in tumor‐associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8+ T‐cell infiltration by recruitment of dendritic cells, and the number of CD8+ T cells was decreased in Kras;JNK1+/− mice compared with Kras;JNK1−/− mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8+ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8+ T cells, which would be expected to enhance antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

et al. 2017

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“…NUMB is a negative regulator of the Notch pathway and Notch plays an important role in T helper (Th) cell immune responses . It has been reported that NUMB is associated with the active phase of relapsing–remitting multiple sclerosis . STX3 is required for chemokine production by mature human mast cells, and altered STX3 expression and localization were found in salivary glands of patients with Sjögren's syndrome .…”

Section: Discussionmentioning

confidence: 99%

Decreased miR‐146 expression in peripheral blood mononuclear cells is correlated with ongoing islet autoimmunity in type 1 diabetes patients 1型糖尿病患者外周血单个核细胞miR‐146表达下调与胰岛持续免疫失衡相关

Yang

Wang

et al. 2014

Journal of Diabetes

111

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“…The expression levels of both CD36 and ABCA1 are also upregulated in demyelinating spinal cord tissue from mice with EAE [88]. In addition, CD36 [122] and apoE [123,124] have recently been associated with the active phase of relapsingremitting MS.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Host Transcriptome from Demyelinating Spinal Cord of Murine Coronavirus-Infected Mice

Elliott

Dragomir

et al. 2013

PLoS ONE

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Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV-induced demyelination. Here, we detail the genes and pathways associated with MHV-induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection.

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Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers

Cited by 35 publications

References 47 publications

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

Decreased miR‐146 expression in peripheral blood mononuclear cells is correlated with ongoing islet autoimmunity in type 1 diabetes patients 1型糖尿病患者外周血单个核细胞miR‐146表达下调与胰岛持续免疫失衡相关

Analysis of the Host Transcriptome from Demyelinating Spinal Cord of Murine Coronavirus-Infected Mice

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