BackgroundNeuroinflammation is implicated in the development and progression of many neurodegenerative diseases. Conditions that lead to a peripheral immune response are often associated with inflammation in the central nervous system (CNS), suggesting a communication between the peripheral immune system and the neuroimmune system. The underlying mechanism of this relationship remains largely unknown; however, experimental studies have demonstrated that exposure to infectious stimuli, such as lipopolysaccharide (LPS) or high-fat diet (HFD) feeding, result in profound peripheral- and neuro-inflammation.MethodsUsing the model of endotoxemia with LPS, we studied the role of serum-derived exosomes in mediating neuroinflammation. We purified circulating exosomes from the sera of LPS-challenged mice, which were then intravenously injected into normal adult mice.ResultsWe found that the recipient mice that received serum-derived exosomes from LPS-challenged mice exhibited elevated microglial activation. Moreover, we observed astrogliosis, increased systemic pro-inflammatory cytokine production, and elevated CNS expression of pro-inflammatory cytokine mRNA and the inflammation-associated microRNA (miR-155) in these recipient mice. Gene expression analysis confirmed that many inflammatory microRNAs were significantly upregulated in the purified exosomes under LPS-challenged conditions. We observed accumulated signaling within the microglia of mice that received tail-vein injections of fluorescently labeled exosomes though the percentage of those microglial cells was found low. Finally, purified LPS-stimulated exosomes from blood when infused directly into the cerebral ventricles provoked significant microgliosis and, to a lesser extent, astrogliosis.ConclusionsThe experimental results suggest that circulating exosomes may act as a neuroinflammatory mediator in systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1038-8) contains supplementary material, which is available to authorized users.

At 24 months after surgery, the cervical disc prosthesis yielded good clinical results while maintaining ROM at the index level. Cervical disc arthroplasty appears to be a viable alternative to ACDF.

Graphical Abstract Highlights d Carbohydrate availability in the gut drives E. coli Nissle adaptation in vivo d Gut monocolonization selects for glycosyl hydrolases enabling population cross-feeding d Mutations that enhance mucin utilization are enriched in lowdiversity guts d Prior antibiotic exposure in conventional guts can lead to evolved probiotic resistance In Brief E. coli Nissle is a probiotic and chassis for engineered biotherapies, but its adaptive behavior in the gut is unclear. Crook et al. report host-mediated selective pressures modulating carbohydrate utilization and metabolism of E. coli Nissle. This in-host evolution also promotes probiotic survival by enabling effective stress responses during colonization. SUMMARYProbiotics are living microorganisms that are increasingly used as gastrointestinal therapeutics by virtue of their innate or engineered genetic function. Unlike abiotic therapeutics, probiotics can replicate in their intended site, subjecting their genomes and therapeutic properties to natural selection. We exposed the candidate probiotic E. coli Nissle (EcN) to the mouse gastrointestinal tract over several weeks, systematically altering the diet and background microbiota complexity. In-transit EcN accumulates genetic mutations that modulate carbohydrate utilization, stress response, and adhesion to gain competitive fitness, while previous exposure to antibiotics reveals an acquisition of resistance. We then leveraged these insights to generate an EcN strain that shows therapeutic efficacy in a mouse model of phenylketonuria and found that it was genetically stable over 1 week, thereby validating EcN's utility as a chassis for engineering. Collectively, we demonstrate a generalizable pipeline that can be applied to other probiotics to better understand their safety and engineering potential. ing of GFP-Tagged EcN, B.W.; Engineering of EcN:PAL2 Strains, Z.C.; Creation, Sharing, and Guidance on Pah enu2 -Mouse Model, S.D.

Autoimmune thyroid disease (AITD) is one of the most common organ‐specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves’ disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor‐specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.

These results support the hypothesis that specific HLA class II alleles might influence the susceptibility or resistance to persistent HCV infection. Both DQB1*0301 and DRB1*1101 are protective alleles and present HCV epitopes more effectively to CD4(+)T lymphocytes than others, and subjects with these two alleles are at a lower risk of developing chronic HCV infection. Large, multi-ethnic confirmatory and well-designed studies are needed to determine the host genetic determinants of HCV infection.