Modulation of innate immune cells by the NAD+ pathway

NAD+ has previously been shown to regulate TNF-α synthesis and TNF-α has been shown to regulate NAD+ homeostasis, thus providing a link between a pro-inflammatory response and redox status. Despite the well-established link between TNF-α and NAD+, the mechanism as to how NAD+ modulates TNF-α release is not fully understood. To achieve this, this link was investigated using THP-1 cell line-derived M1-like (pro-inflammatory) and M2-like (anti-inflammatory) macrophages using PMA and vitamin D3, respectively. NAD+ levels differed markedly between M1-like and M2-like macrophages, with M1-like having much higher basal levels. LPS increases NAD+ levels and TNF-α secretion in M1-like but not M2-like cells. In an effort to investigate the source of the NAD+ levels and the association with TNF-α release, three inhibitors (FK866, DPI and 1D-MT) were used. Following stimulation, NAD+ is produced partially via NADH oxidation and partially through NAD+ synthesis. Both DPI and FK866 reduced TNF-α secretion with DPI showing the largest effect. The two phenotypes showed differential profiles of NAD+ homeostasis gene expression compared with each other and with the progenitor THP-1 in both resting and activated states. While IDO expression was induced in both phenotypes, CD38 and NAMPT were upregulated in M1-like cells whereas CD157 was upregulated in M2-like cells. LPS induced M1-like cells to up-regulate CD38 and CD157 and down-regulate NAMPT unlike M2-like cells which up-regulated NAMPT and CD38 and down-regulated CD157. M1s increased glycolysis activity whereas conversely, decreased oxidative metabolism during LPS stimulation confirming previous findings showing that classical M1s are predominantly glycolytic. Collectively, these data suggest that the relationship between NAD+ levels and pro-/anti-inflammatory responses is complex and may be regulated via a combination of pathways. These findings open the possibility of pharmacological manipulation of NAD+ synthesis as a way of selectively modulating macrophage responses which may be beneficial for the development of therapeutics targeting inflammatory diseases.College of Science, Al-Qadisiyah University, Ministry of Higher Educatio

Intracellular NAD+ levels are associated with LPS-induced TNF-α release in pro-inflammatory macrophages

Bacterial lipopolysaccharide induces changes in intracellular NAD+ levels in a pro-inflammatory, but not an anti-inflammatory, macrophage model that are correlated with the release of the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α).</jats:p

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed