Transient Receptor Potential Vanilloid 4-Dependent Microglial Function in Myelin Injury and Repair.

Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as environmental sensors, and are involved in calcium homeostasis for a variety of cells. TRPV4 modulates myeloid cell phagocytosis in the periphery and microglial motility in the central nervous system. We hypothesized that TRPV4 deletion would alter microglia phagocytosis in vitro and lessen disease activity and demyelination in experimental autoimmune encephalitis (EAE) and cuprizone-induced demyelination. We found that genetic deletion of TRPV4 led to increased microglial phagocytosis in vitro but did not alter the degree of demyelination or remyelination in the cuprizone mouse model of MS. We also found no difference in disease in EAE following global or microglia-specific deletion of Trpv4. Additionally, lesioned and normal appearing white matter from MS brains exhibited similar TRPV4 expression compared to healthy brain tissue. Taken together, these findings indicate that TRPV4 modulates microglial activity but does not impact disease activity in mouse models of MS, suggesting a muted and/or redundant role in MS pathogenesis.

The Role of B Cells in Primary Progressive Multiple Sclerosis.

The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it's unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS.

The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis.

This article examines the current use and future implications of stem cell therapy in treating Multiple Sclerosis (MS). MS is the most common neurological disease in young adults, affecting approximately two million people worldwide. Currently there is no cure for MS. The standard treatment of MS involves disease-modifying drugs, which work to alleviate the symptoms of MS. However, these drugs carry adverse side effects and are ineffective in preventing disease progression in many MS patients. Hematopoietic stem cell transplantation (HSCT) was first used in 1995 to treat patients with severe rapidly progressing MS. The HSCT treatment protocol has evolved into a less intense conditioning regimen that is currently demonstrating efficacy in treating patients with variable disease severity-with best results in early-stage rapidly progressing MS patients with active CNS inflammation. Mesenchymal stem cell therapy (MSCT) is an experimental stem cell therapy currently undergoing clinical trials. Animal models and early clinical trials have shown promise that MSCT might be a low risk treatment to precipitate neuroregeneration and immunomodulation in MS patients. Specifically, neuroprogenitor and placental-derived mesenchymal stem cells offer the best hope for a practical treatment for MS. Stem cell therapy, and perhaps a combinatorial therapeutic approach, holds promise for a better treatment for MS.