Elevated Levels of Proinflammatory Cytokines in Cerebrospinal Fluid of Multiple Sclerosis Patients

Хайбуллин, Т И; Ivanova, Vilena V.; Мартынова, Е. В.; Черепнев, Г. В.; Хабиров, Ф. А.; Гранатов, Е В; Rizvanov, Albert A.; Khaiboullina, Svetlana F.

doi:10.3389/fimmu.2017.00531

Cited by 123 publications

(108 citation statements)

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“…MS is a chronic inflammatory demyelination disease. Evidence suggests that leukocytes cross the blood–brain barrier (BBB) and localize in lesions of the CNS (Khaibullin et al, ). To further detect the effect of miR‐1896 and miR‐409‐3p on the infiltration of inflammatory cells in the CNS of EAE mice, H&E staining was performed in sections of brain tissues and spinal cords.…”

Section: Resultsmentioning

confidence: 99%

MiR‐409‐3p and MiR‐1896 co‐operatively participate in IL‐17‐induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling

Liu

Feng

Yang

et al. 2018

Glia

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Th17 cells and interleukin‐17 (IL‐17) have been found to play an important role in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Response to IL‐17, reactive astrocytes accompany with immune cells infiltration and axonal damage in MS/EAE. However, the role and the regulatory mechanism of IL‐17‐activated astrocytes in inflammation and in the EAE process still remain largely unknown. Here, we elucidated that miR‐409‐3p and miR‐1896, as co‐upregulated microRNAs in activated astrocytes and in EAE mice, targeted suppressor of cytokine signaling proteins 3 (SOCS3). Overexpression of miR‐409‐3p or miR‐1896 significantly reduced SOCS3 expression and increased phosphorylation of STAT3 as well as induced the inflammatory cytokines production (IL‐1β, IL‐6, IP‐10, MCP‐1, and KC), CD4+T cells migration and demyelination, in turn aggravating EAE development. Importantly, the effects of co‐overexpression of miR‐409‐3p and miR‐1896 in vitro or in vivo are strongly co‐operative. In contrast, simultaneously silenced miR‐409‐3p and miR‐1896 co‐operatively ameliorates inflammation and demyelination in the central nervous system of EAE mice. Collectively, our findings highlight that miR‐409‐3p and miR‐1896 co‐ordinately promote the production of inflammatory cytokines in reactive astrocytes through the SOCS3/STAT3 pathway and enhance reactive astrocyte‐directed chemotaxis of CD4+T cells, leading to aggravate pathogenesis in EAE mice. Co‐inhibition of miR‐409‐3p and miR‐1896 may be a therapeutic target for treating MS and neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

MiR‐409‐3p and MiR‐1896 co‐operatively participate in IL‐17‐induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling

Liu

Feng

Yang

et al. 2018

Glia

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“…In conjunction with our data showing decreased expression of BRCC3 at the lesion site of the brain sections prepared from MS patients, an unresolved question is whether the demyelinating micro‐environmental factor(s) inhibited BRCC3 expression in OPCs or in OLs. Changes in the levels of several cytokines have been detected in the CSF from patients with MS (Khaibullin et al, ). For instance, the level of IL‐1β was decreased in the CSF from patients with MS compared to the control group (Khaibullin et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Changes in the levels of several cytokines have been detected in the CSF from patients with MS (Khaibullin et al, ). For instance, the level of IL‐1β was decreased in the CSF from patients with MS compared to the control group (Khaibullin et al, ). BRCC3 expression was upregulated in the OL cultures treated with IL‐1β in the present study (Figure S5), indicating that the downregulation of BRCC3 at the lesion site might be due to the decrease in IL‐1β levels.…”

Section: Discussionmentioning

confidence: 99%

“…BRCC3, BRCA1/BRCA2-containing complex subunit 3; MS, multiple sclerosis; OL, oligodendrocytes environmental factor(s) inhibited BRCC3 expression in OPCs or in OLs. Changes in the levels of several cytokines have been detected in the CSF from patients with MS (Khaibullin et al, 2017). For instance, the level of IL-1β was decreased in the CSF from patients with MS compared to the control group (Khaibullin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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BRCA1/BRCA2‐containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine 63‐linked ubiquitination

Wang

Deneen

Tzeng

2019

Glia

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Oligodendrocytes (OLs) provide the myelin sheath surrounding axons that propagates action potentials in the central nervous system (CNS). The metabolism of myelinated membranes and proteins is strictly regulated in the OLs and is closely associated with OL differentiation and maturation. The ubiquitination‐associated proteasome and endosomal system have not yet been well studied during OL differentiation and maturation. Here, we determined the functions of the Lys63‐linked ubiquitination (K63Ub) and K63‐specific deubiquitination (DUB) systems regulated by BRCA1/BRCA2‐containing complex subunit 3 (BRCC3) during OL differentiation. The competitive inhibition of K63Ub by overexpression of mutant ubiquitin (K63R) in oligodendrocyte precursor cells (OPCs) indicated that the two major CNS myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), were upregulated in OLs derived from K63R OPCs. In contrast, the knockdown of BRCC3 (BRCC3‐KD) through the application of lentivirus‐mediated shRNA delivery system into OPCs suppressed OL differentiation by decreasing MBP expression and PLP production. Further immunoprecipitation assays revealed higher levels of sphingolipid GalC, MBP, and PLP, which were associated with K63Ub‐immunoprecipitants and detected in endosome/lysosomal compartments, in BRCC3‐KD OLs than those in OLs transfected with the scrambled shRNA (scramble OLs). The differentiation of OLs from BRCC3‐KD OPCs was impaired in the demyelinating corpus callosum of rats receiving a cuprizone‐containing diet. In the demyelinating tissues from human patients suffering from multiple sclerosis, we detected a decreased number of BRCC3‐expressing OLs at the lesion site, accompanied by a greater number of OLs expressing EEA1 and K63Ub at high levels. Altogether, the counterbalance of the K63Ub machinery and BRCC3‐triggered DUB machinery are important for the cellular trafficking of myelin proteins and OL differentiation.

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“…Arachidonic acid is a membrane omega-6 fatty acid molecule released in the cytoplasm by the hydrolytic activity of the cytosolic phospholipase A 2 (cPLA 2 ) (Figure 1). It has been shown that the concentration of several molecules that activate cPLA 2 , such as reactive oxygen species and cytokines, is increased in multiple sclerosis (11)(12)(13)(14). After being released into the cytoplasm, arachidonic acid is metabolized by the activity of cyclooxygenases (COXs) 1 and 2 into prostacyclins, prostaglandins (PGs), and thromboxanes (TXs), and by the lipoxygenases (LOXs), 5-LOX, 12-LOX and/or 15-LOX into leukotrienes (LTs) and lipoxins (LXs).…”

Section: Activation Of the Arachidonic Acid Cascade In Multiple Sclermentioning

confidence: 99%

Pathogenesis and Progression of Multiple Sclerosis: The Role of Arachidonic Acid–Mediated Neuroinflammation

Palumbo

2017

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

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Multiple sclerosis is characterized by inflammatory processes occurring within the central nervous system. In multiple sclerosis, inflammation could be either a physiological response secondary to the immune system activation or a phenomenon triggered by primary cytodegeneration of neurons and/ or oligodendrocytes without the involvement of immune cells. The arachidonic acid metabolism is activated via cyclooxygenases (COXs) and lipoxygenases (LOXs) in postmortem brain samples and in the cerebrospinal fluid of multiple sclerosis patients. It has been hypothesized that the arachidonic acid-mediated neuroinflammation could play a role in the pathogenic mechanisms triggering demyelination, oligodendrocyte loss, axonal pathology and, ultimately, motor dysfunctions, which are hallmarks of multiple sclerosis. COX-2 and 5-LOX selective inhibitors efficiently inhibit each of the hallmarks mentioned above in different animal models of multiple sclerosis. Thus, it is suggested that the arachidonic acid pathway represents a potential pharmacological target to ameliorate multiple sclerosis pathology and symptoms.

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Elevated Levels of Proinflammatory Cytokines in Cerebrospinal Fluid of Multiple Sclerosis Patients

Cited by 123 publications

References 47 publications

MiR‐409‐3p and MiR‐1896 co‐operatively participate in IL‐17‐induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling

MiR‐409‐3p and MiR‐1896 co‐operatively participate in IL‐17‐induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling

BRCA1/BRCA2‐containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine 63‐linked ubiquitination

Pathogenesis and Progression of Multiple Sclerosis: The Role of Arachidonic Acid–Mediated Neuroinflammation

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