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Traumatic spinal cord injury (SCI) is characterized by severe neuroinflammation and hampered neuroregeneration, which often leads to permanent neurological deficits. Current therapies include decompression surgery, rehabilitation, and in some instances, the use of corticosteroids. However, the golden standard of corticosteroids still achieves minimal improvements in functional outcomes. Therefore, new strategies tackling the initial inflammatory reactions and stimulating endogenous repair in later stages are crucial to achieving functional repair in SCI patients. Cyclic adenosine monophosphate (cAMP) is an important second messenger in the central nervous system (CNS) that modulates these processes. A sustained drop in cAMP levels is observed during SCI, and elevating cAMP is associated with improved functional outcomes in experimental models. cAMP is regulated in a spatiotemporal manner by its hydrolyzing enzyme phosphodiesterase (PDE). Growing evidence suggests that inhibition of cAMP-specific PDEs (PDE4, PDE7, and PDE8) is an important strategy to orchestrate neuroinflammation and regeneration in the CNS. Therefore, this review focuses on the current evidence related to the immunomodulatory and neuroregenerative role of cAMP-specific PDE inhibition in the SCI pathophysiology. The APC was funded by FWO (G042121N and 1209123N)

Additional file 1. Figure S1. Example of the gating strategy used to distinguish different immune cell subsets. Representative spleen sample from a PBS-treated hu/m TNFR2-ki mouse sacrificed at 25 days post immunization. Figure S2. Blocking TNFR1 with and without a TNFR2 agonist limits EAE development by decreasing demyelination while increasing lymphocyte numbers in the spinal cord. Figure S3. EHD2-scTNFR2 and ATROSIMAB treatments increase the level of anti-drug antibodies in serum but do not affect clinical EAE development. Figure S4. Frequency of immune cell subsets in inguinal lymph nodes and spleen. Figure S5. APP staining of spinal cord sections from representative mice from the acute cohort shows that axonal degeneration increases similarly to demyelination. Table S1. Primary antibodies used for immunohistochemistry and flow cytometry. Table S2. Clinical EAE development in hu/m TNFR1-ki x hu/m TNFR2 -ki mice treated either with PBS, a human TNFR2 agonist (EHD2-scTNFR2) and/or a human TNFR1 antagonist (ATROSIMAB).

Introduction In the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation of Id2/Id4 is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity.Methods We compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n=9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation.Results Our data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation of MBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region of MBP, using epigenetic editing, we show that cellular differentiation can be bidirectionally manipulated using the CRISPR-dCas9-DNMT3a/TET1 system in vitro.Conclusion Our data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination related genes. Altering the epigenetic status of MBP can restore the differentiation capacity of OPCs and possibly boost (re)myelination.Competing Interest StatementThe authors have declared no competing interest.

MS is an inflammatory disorder of the brain and spinal cord, where the body’s immune system incorrectly attacks its central nervous system (CNS), causing variable and unpredictable symptoms. Some examples of clinical symptoms include slurred speech, blurred vision, loss of balance, poor coordination, tremors, numbness, extreme fatigue, problems with memory and concentration, paralysis, and blindness. MS affects more than 700,000 people living in Europe, two to three times as many women as men, and is most often diagnosed in people aged 20-40 years. MS varies in severity, from mild symptoms to a disabling condition. The overall cost of MS in Europe to health and social care is estimated to be 15 billion euros per year. There is an urgent need to speed-up the prognosis and treatment of people with MS (PwMS). The time needed to find the matching DMT for a given PwMS is mostly based on clinical practice trial and error. Moreover, a treatment that was initially satisfactory might eventually become ineffective because of disease progression. Delays in identifying treatment failure and selecting an appropriate next-line DMT will further degrade patients' quality of life. To date, 14 DMTs have been approved for relapsing-remitting MS based on their efficacy in randomized controlled trials (RCTs). RCTs are accepted as the gold standard for assessing the efficacy and safety of any new drug and are conducted in a controlled setting with well-defined homogeneous patient populations selected through strict inclusion criteria. These cohorts do not necessarily represent MS in real life, and conclusions made from these RCTs, therefore, do not always translate to the individual patient. High performance MS-specific decision support systems are needed to support treatment decision-making by neurologists and regulators (= the right DMT for the right patient). And we need these decision-support systems to function in what we call a “real-world” setting. Therefore, insights should be gained using “real-world-data” (RWD). Real-world data (RWD) are defined as data derived from a number of sources that are associated with outcomes in a heterogeneous patient population representing the real-world settings (e.g., data collected by physicians in standard clinical care and longitudinal follow-up. In this project, we aim to speed up the search for the optimal DMT by using real-world data. Three main objectives are identified: 1. Identification of lesions that result in functional damage 2. Prediction of long-term disability progression 3. Discovery of biomarkers that are sensitive to disease progression on short timescales. We hypothesize that overlaying evoked potential (EP) features (epomics) with quantitative image analysis (radiomics) can improve the performance of these three tasks, compared to statistical models that only use classical, well-known features (such as the number of lesions for MRI and latency for EPTS).

Once regarded as an experimental artefact, cytotoxic CD4(+) T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naive CD4(+) T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies. CH received funds from Stichting MS Research. GD received funds from Charcot Stichting. NH received funds from FWO and Charcot Stichting. BB received funds from Charcot Stichting, MSIF, MoveS, and Stichting MS Research