CNS Remyelination and the Innate Immune System.

A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune-mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease.The authors would particularly like to acknowledge the support of the UK MS Society, The Jean Shanks Foundation and MedImmune.This is the author accepted manuscript. The final version is available from Frontiers via http://dx.doi.org/10.3389/fcell.2016.0003

Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases

The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.This work was supported by grants from UK Multiple Sclerosis Society, The British Trust for the Myelin Project, MedImmune, The Adelson Medical Research Foundation, Wellcome Trust, BBSRC, the Leverhulme Trust and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute. CEM was supported by grants from the Jean Shanks Foundation and the James Baird Fund, AGF was supported by an ECTRIMS fellowship and OBZ received a BIRAX fellowship

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease

Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation

Clinical implications of myelin regeneration in the central nervous system.

Amongst strategies to repair the brain, myelin repair offers genuine cause for optimism. Myelin, which sheaths most axons in the central nervous system (CNS), is vital for normal neurological function, as demonstrated by the functional deficits that accrue when it is absent in a range of debilitating myelin diseases. Following demyelination, post-mortem and imaging studies have shown that extensive regeneration of myelin is possible in the human brain. Over recent decades preclinical research has given us a strong understanding of the biology of myelin regeneration, opening up several exciting therapeutic opportunities that are on the cusp of clinical translation. Areas covered: This review discusses diseases that compromise the function of myelin, the endogenous capacity of the CNS to regenerate myelin, and why this sometimes fails. We then outline the extensive progress that has been made towards therapies that promote the regeneration of myelin. Expert commentary: Finally, a commentary on the first examples of these therapies to reach human patients and the evidence base that supports them, giving our opinion on where attention should be focused going forward is provided

The Modern Medical Student Manual : a book review

Chris Lovejoy’s book ‘The Modern Medical Student Manual’ combines personal anecdote and a philosophical approach that stands out for the shortness of its nature and the uniqueness of its disposition. There is something to be said for a short guide for medical students written by a recently graduated Foundation Year doctor. While the book occasionally falls short of the easy ebb and flow of other authors in the field, and perhaps, at times, attempts to stretch beyond its reach, it more than makes up in the authenticity of its voice and the quality of its personal reflection

Clinical biomarker-based biological aging and risk of cancer in the UK Biobank

Background: Despite a clear link between aging and cancer, there has been inconclusive evidence on how biological age (BA) may be associated with cancer incidence. Methods: We studied 308,156 UK Biobank participants with no history of cancer at enrolment. Using 18 age-associated clinical biomarkers, we computed three BA measures (Klemera-Doubal method [KDM], PhenoAge, homeostatic dysregulation [HD]) and assessed their associations with incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, and melanoma) using Cox proportional-hazards models. Results: A total of 35,426 incident cancers were documented during a median follow-up of 10.9 years. Adjusting for common cancer risk factors, 1-standard deviation (SD) increment in the age-adjusted KDM (hazard ratio = 1.04, 95% confidence interval = 1.03–1.05), age-adjusted PhenoAge (1.09, 1.07–1.10), and HD (1.02, 1.01–1.03) was significantly associated with a higher risk of any cancer. All BA measures were also associated with increased risks of lung and colorectal cancers, but only PhenoAge was associated with breast cancer risk. Furthermore, we observed an inverse association between BA measures and prostate cancer, although it was attenuated after removing glycated hemoglobin and serum glucose from the BA algorithms. Conclusions: Advanced BA quantified by clinical biomarkers is associated with increased risks of any cancer, lung cancer, and colorectal cancer.publishedVersionPeer reviewe