Epigenetic insights into multiple sclerosis disease progression.

Multiple sclerosis (MS), a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system, is today a leading cause of unpredictable lifelong disability in young adults. The treatment of patients in progressive stages remains highly challenging, alluding to our limited understanding of the underlying pathological processes. In this review, we provide insights into the mechanisms underpinning MS progression from a perspective of epigenetics, that refers to stable and mitotically heritable, yet reversible, changes in the genome activity and gene expression. We first recapitulate findings from epigenetic studies examining the brain tissue of progressive MS patients, which support a contribution of DNA and histone modifications in impaired oligodendrocyte differentiation, defective myelination/remyelination and sustained neuro-axonal vulnerability. We next explore possibilities for identifying factors affecting progression using easily accessible tissues such as blood by comparing epigenetic signatures in peripheral immune cells and brain tissue. Despite minor overlap at individual methylation sites, nearly 30% of altered genes reported in peripheral immune cells of progressive MS patients were found in brain tissue, jointly converging on alterations of neuronal functions. We further speculate about the mechanisms underlying shared epigenetic patterns between blood and brain, which likely imply the influence of internal (genetic control) and/or external (e.g. smoking and ageing) factors imprinting a common signature in both compartments. Overall, we propose that epigenetics might shed light on clinically relevant mechanisms involved in disease progression and open new avenues for the treatment of progressive MS patients in the future.

Decreased Expression of IFNG-AS1, IFNG and IL-1B Inflammatory Genes in Medicated Schizophrenia and Bipolar Patients.

Although aberrant expression of cytokines such as IL-1B and IFNG in blood from psychiatric patients supports a role of inflammation in the pathogenesis of the disease, little is known about mechanisms underlying their regulation. We aimed to evaluate the putative role of IFNG-AS1 long non-coding RNA (lncRNA) in controlling of IFNG locus in patients with schizophrenia (SZ) and bipolar (BP). We analysed the expression levels of IFNG-AS1 long non-coding RNA, and IFNG and IL-1B mRNAs in blood cells from 27 SZ- and 30 BP-medicated patients and in 32 healthy controls. Our data showed that IFNG-AS1 expression dramatically decreased in BP and SZ patients compared with controls and was significantly correlated with IFNG expression in patients specifically. Transcript levels of IL-1B were also significantly reduced in BP and SZ patients compared with controls. No significant differences in the expression of IFNG-AS1, IFNG and IL-1B genes were found between patients with BP and SZ. Our data shed further light on the potential role of inflammation, and more particularly inflammatory lncRNAs, in SZ and BP diseases and their pharmacological treatment.

The CCN family: a new class of inflammation modulators?

Uncontrolled or sustained inflammation is the underlying cause of or actively contributes to the progression of many chronic pathologies such as atherosclerosis, arthritis, or neuroinflammatory diseases. Matricellular proteins of the CCN family (CYR61/CTGF/NOV) have emerged as localized multitasking signal integrators. These structurally conserved secreted proteins specifically interact with and signal through various extracellular partners, in particular integrins, which enable them to play crucial roles in various processes including development, angiogenesis, wound healing and diseases such as fibrosis, vascular disease and cancer. In this review, we discuss the possibility that the CCN family members could represent a putative new class of modulators of inflammation. In this context, we focused on their relationship with cytokines and chemokines. In vitro, CCN expression is finely regulated by diverse inflammatory mediators including cytokines (TNFα, IL1ß, TGF-ß), small factors such as prostaglandins, nitric oxide, histamine and serotonin, and extracellular matrix enzymes. In addition, CCN proteins acting alone or in concert with their specific partners appear to be potent regulators of the production of cytokines and chemokines in a context-dependent manner. Finally, emerging studies suggest a potential role for CCN proteins in chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, inflammatory kidney diseases and neuroinflammatory pathologies such as Alzheimer's disease. CCN members could therefore represent new potential therapeutic targets for drug development against such diseases.

NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through beta1 and beta5 integrins.

Increasing evidence suggests that CCN matricellular proteins play important roles in inflammation. One of the major cell types that handle inflammation in the brain is the astrocyte, which, upon activation, dramatically increases its production of cytokines and chemokines. Here, we report that NOV/CCN3, added to primary cultured rat brain astrocytes, markedly increased the expression of CCL2 and CXCL1 chemokines, as indicated by ELISA and RT-qPCR assays. This effect was selective, as the production of thirteen other cytokines and chemokines was not affected by NOV. NOV expression by astrocytes was demonstrated by immunocytochemistry and Western blot analysis, and astrocyte transfection with NOV small interfering RNA (siRNA) markedly decreased CXCL1 and CCL2 production, indicating that endogenous NOV played a major role in the control of astrocytic chemokine synthesis. NOV was shown to mediate several of its actions through integrins. Here, we observed that siRNAs against integrins beta1 and beta5 decreased basal and abrogated NOV-stimulated astrocyte expression of CCL2 and CXCL1, respectively. Using a panel of kinase inhibitors, we demonstrated that NOV action on CCL2 and CXCL1 production involved a Rho/ROCK/JNK/NF-kappaB and a Rho/qROCK/p38/NF-kappaB pathway, respectively. Thus, distinct integrins and signaling mechanisms are involved in NOV-induced production of CCL2 and CXCL1 in astrocytes. Finally, astrocytic expression of NOV was detected in rat brain tissue sections, and NOV intracerebral injection increased CCL2 and CXCL1 brain levels in vivo. Altogether, our data shed light on the signaling pathways operated by NOV and strongly suggest that NOV mediates astrocyte activation and, therefore, might play a role in neuroinflammation.