Vitamin D Regulates MerTK-Dependent Phagocytosis in Human Myeloid Cells.

Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis. The major circulating metabolite of vitamin D (25-hydroxyvitamin D) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1 In multiple sclerosis lesions, the tyrosine kinase MerTK expressed by myeloid cells regulates phagocytosis of myelin debris and apoptotic cells that can accumulate and inhibit tissue repair and remyelination. In this study, we explored the effect of calcitriol on homeostatic (M-CSF, TGF-ß-treated) and proinflammatory (GM-CSF-treated) human monocyte-derived macrophages and microglia using RNA sequencing. Transcriptomic analysis revealed significant calcitriol-mediated effects on both Ag presentation and phagocytosis pathways. Calcitriol downregulated MerTK mRNA and protein expression in both myeloid populations, resulting in reduced capacity of these cells to phagocytose myelin and apoptotic T cells. Proinflammatory myeloid cells expressed high levels of CYP27B1 compared with homeostatic myeloid cells. Only proinflammatory cells in the presence of TNF-α generated calcitriol from 25-hydroxyvitamin D, resulting in repression of MerTK expression and function. This selective production of calcitriol in proinflammatory myeloid cells has the potential to reduce the risk for autoantigen presentation while retaining the phagocytic ability of homeostatic myeloid cells.

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

Novel Molecular Leads for the Prevention of Damage and the Promotion of Repair in Neuroimmunological Disease.

Neuroinflammation is a prominent pathological feature of all neuroimmunological diseases, including, but not limited to, multiple sclerosis (MS), myasthenia gravis, neuromyelitis optica, and Guillain-Barré syndrome. All currently-approved therapies for the treatment of these diseases focus on controlling or modulating the immune (innate and adaptive) responses to limit demyelination and neuronal damage. The primary purpose of this review is to detail the pre-clinical data and proposed mechanism of action of novel drugs currently in clinical trial, with a focus on novel compounds that promote repair and regeneration in the central nervous system (CNS). As the most recent advances have been made in the field of MS research, this review will focus primarily on this disease and its animal models. However, these compounds are likely to be effective for a range of indications with a neuroinflammatory component. Traditionally, MS was thought to proceed through two distinct phases. The first, predominantly inflammatory stage, is characterized by acute episodes of clinical relapse, followed by periods of partial or total recovery with an apparent absence of overall disease progression. In the vast majority of patients, this relapsing-remitting disease subsequently progresses into a second more chronic, neurodegenerative phase, which is characterized by oligodendrocyte damage and axonal destruction leading to brain atrophy and an accumulation of disability. Recent work has shown that rather than occurring independently, both the inflammatory and degenerative phases may run concurrently. This, combined with evidence that early therapeutic intervention slows accumulation of disability and delays progression, highlights the need for novel therapeutic approaches that promote repair and regeneration early in the disease trajectory. Such compounds may be used as monotherapies or in conjunction with classical anti-inflammatory therapies. This review will highlight novel therapies currently in clinical trial, and likely to appear in clinical practice in the near future, focusing on compounds that target the immune system and/or enhance endogenous repair mechanisms in the CNS.