microRNA-146a modulates behavioural activity, neuroinflammation, and oxidative stress in adult mice.

Small non-coding miRNA act as key regulators of several physiological processes due to their ability to interact with numerous target mRNA within a network. Whilst several miRNA can act in concert to regulate target mRNA expression, miR-146a has emerged as a critical modulator of inflammation by targeting key upstream signalling proteins of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and reductions in this miRNA have been observed in several neurological and neurodegenerative disorders. However, a targeted assessment of behaviour and neural tissues following the loss of miR-146a has not been documented. In this study, we examined the behavioural and neuroinflammatory phenotype of mice lacking miR-146a to determine the role of this miRNA in neurological function. Adult miR-146a-/- mice displayed no overt developmental phenotype with the exception of enlarged spleens. Behavioural testing revealed a mild but significant reduction in exploratory locomotor activity and increase in anxiety-like behaviour, with no changes in short-term spatial memory, fear conditioning, or sensorimotor gating. In the brain, the lack of miR-146a resulted in a significant compensatory miR-155 expression with no significant changes in expression of the target Interleukin 1 Receptor Associated Kinase (Irak) gene family. Despite these effects on upstream NF-κB mediators, downstream expression of cytokine and chemokine messengers was significantly elevated in miR-146a-/- mice compared to wild-type controls. Moreover, this increase in inflammatory cytokines was observed alongside an induction of oxidative stress, driven in part by nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, and included reduced thiol antioxidant concentrations and increased oxidised protein carbonyl concentrations. In female miR-146a mice, this increase in oxidative stress resulted in an increased expression of superoxide dismutase 1 (SOD1). Together, this suggests miR-146a plays a key role in regulating inflammation even in the absence of inflammatory stimuli and reduced levels of this miRNA have the capacity to induce limited behavioural effects whilst exacerbating both inflammation and oxidative stress in the brain.

Extracellular vesicles with diagnostic and therapeutic potential for prion diseases.

Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrPC) to the neurotoxic pathogenic form (PrPTSE) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrPC is transformed to the misfolded, aggregation-prone and pathogenic PrPTSE remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrPTSE accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrPTSE transmission in PrD. This review will comprehensively discuss PrPTSE transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.

Repeated acute stress modulates hepatic inflammation and markers of macrophage polarisation in the rat.

Bidirectional communication between the neuroendocrine stress and immune systems permits classically anti-inflammatory glucocorticoids to exert pro-inflammatory effects in specific cells and tissues. Liver macrophages/Kupffer cells play a crucial role in initiating inflammatory cascades mediated by the release of pro-inflammatory cytokines following tissue injury. However, the effects of repeated acute psychological stress on hepatic inflammatory phenotype and macrophage activation state remains poorly understood. We have utilised a model of repeated acute stress in rodents to observe the changes in hepatic inflammatory phenotype, including anti-inflammatory vitamin D status, in addition to examining markers of classically and alternatively-activated macrophages. Male Wistar rats were subjected to control conditions or 6 h of restraint stress applied for 1 or 3 days (n = 8 per group) after which plasma concentrations of stress hormone, enzymes associated with liver damage, and vitamin D status were examined, in addition to hepatic expression of pro- and anti-inflammatory markers. Stress increased glucocorticoids and active vitamin D levels in addition to expression of glucocorticoid alpha/beta receptor, whilst changes in circulating hepatic enzymes indicated sustained liver damage. A pro-inflammatory response was observed in liver tissues following stress, and inducible nitric oxide synthase being observed within hepatic macrophage/Kupffer cells. Together, this suggests that stress preferentially induces a pro-inflammatory response in the liver.