Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.

Vitamin C and E supplementation and high intensity interval training induced changes in lipid profile and haematological variables of young males.

High intensity interval training (HIIT) causes oxidative stress and haematological alteration. Present study was aimed to evaluate the effect of 8 weeks' supplementation of vitamin C and E on HIIT induced changes in lipid profile parameters and haematological variables. Hundred six male adolescent players were randomly assigned into five age-matched groups, i.e., Control (no exercise+placebo), HIIT (placebo), HIIT â€‹+ â€‹vitamin-C (1 000 â€‹mg/day), HIIT â€‹+ â€‹vitamin-E 400 IU/day) and combined HIIT â€‹+ â€‹vitamin C and E. Morning and evening sessions (90 â€‹min) of HIIT included 4 phases (15 â€‹min each) with 3 sets (4 â€‹min each). Each 4 â€‹min HIIT set consisted of 2 â€‹min intense sprint workout (90%-95% of heart rate maximum [HRmax]) followed by 1 â€‹min active recovery (60%-70% HRmax) followed by 1 â€‹min of complete rest (1:1 work-rest ratio). Lipid profile parameters, haematological variables, endurance capacity and vertical jump were evaluated by standard protocols. Significant decrease in body weight, fat%, total cholesterol, triglyceride, Total Cholesterol/High Density Lipoprotein-Cholesterol and significant increase in High Density Lipoprotein-Cholesterol, maximal oxygen consumption, vertical jump were observed for all four intervention groups. White blood cell count, red blood cell count, haemoglobin percentage and haematocrit values were significantly decreased while platelet count and platelet-to-leukocyte ratio (PLR) ratio were increased significantly only for HIIT group. Blood level of tocopherol and ascorbic acid was significantly increased (values were within the normal range) in all the respective vitamin supplemented groups. Supplementation of vitamin C and E secures health protection with suppressed haemolysis and improved inflammatory blood variables with enhanced explosive leg strength and lipid profile parameters without any concomitant change in endurance capacity.

Role of vitamin D in regulating COVID-19 severity-An immunological perspective.

Vitamin D, a key nutrient/prohormone classically associated with skeletal health, is also an important immunomodulator, with pleotropic effects on innate and adaptive immune cells. Outcomes of several chronic, autoimmune, and infectious diseases are linked to vitamin D. Emergent correlations of vitamin D insufficiency with coronavirus-induced disease 2019 (COVID-19) severity, alongside empirical and clinical evidence of immunoregulation by vitamin D in other pulmonary diseases, have prompted proposals of vitamin D supplementation to curb the COVID-19 public health toll. In this review paper, we engage an immunological lens to discuss potential mechanisms by which vitamin D signals might regulate respiratory disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections, vis a vis other pulmonary infections. It is proposed that vitamin D signals temper lung inflammatory cascades during SARS-CoV2 infection, and insufficiency of vitamin D causes increased inflammatory cytokine storm, thus leading to exacerbated respiratory disease. Additionally, analogous to studies of reduced cancer incidence, the dosage of vitamin D compounds administered to patients near the upper limit of safety may serve to maximize immune health benefits and mitigate inflammation and disease severity in SARS-CoV2 infections. We further deliberate on the importance of statistically powered clinical correlative and interventional studies, and the need for in-depth basic research into vitamin D-dependent host determinants of respiratory disease severity.

Role of vitamin D in cytotoxic T lymphocyte immunity to pathogens and cancer.

The discovery of vitamin D receptor (VDR) expression in immune cells has opened up a new area of research into immunoregulation by vitamin D, a niche that is distinct from its classical role in skeletal health. Today, about three decades since this discovery, numerous cellular and molecular targets of vitamin D in the immune system have been delineated. Moreover, strong clinical associations between vitamin D status and the incidence/severity of many immune-regulated disorders (e.g. infectious diseases, cancers and autoimmunity) have prompted the idea of using vitamin D supplementation to manipulate disease outcome. While much is known about the effects of vitamin D on innate immune responses and helper T (T(H)) cell immunity, there has been relatively limited progress on the frontier of cytotoxic T lymphocyte (CTL) immunity--an arm of host cellular adaptive immunity that is crucial for the control of such intracellular pathogens as human immunodeficiency virus (HIV), tuberculosis (TB), malaria, and hepatitis C virus (HCV). In this review, we discuss the strong historical and clinical link between vitamin D and infectious diseases that involves cytotoxic T lymphocyte (CTL) immunity, present our current understanding as well as critical knowledge gaps in the realm of vitamin D regulation of host CTL responses, and highlight potential regulatory connections between vitamin D and effector and memory CD8 T cell differentiation events during infections.