Inflammation and blood-brain barrier breach remote from the primary injury following neurotrauma

Background: Following injury to the central nervous system, increased microglia, secretion of pro- and anti-inflammatory cytokines, and altered blood-brain barrier permeability, a hallmark of degeneration, are observed at and immediately adjacent to the injury site. However, few studies investigate how regions remote from the primary injury could also suffer from inflammation and secondary degeneration. Methods: Adult female Piebald-Viral-Glaxo (PVG) rats underwent partial transection of the right optic nerve, with normal, age-matched, unoperated animals as controls. Perfusion-fixed brains and right optic nerves were harvested for immunohistochemical assessment of inflammatory markers and blood-brain barrier integrity; fresh-frozen brains were used for multiplex cytokine analysis. Results: Immediately ventral to the optic nerve injury, immunointensity of both the pro-inflammatory biomarker inducible nitric oxide synthase (iNOS) and the anti-inflammatory biomarker arginase-1 (Arg1) increased at 7 days post-injury, with colocalization of iNOS and Arg1 immunoreactivity within individual cells. CD11b+ and CD45+ cells were increased 7 days post-injury, with altered BBB permeability still evident at this time. In the lower and middle optic tract and superior colliculus, IBA1+ resident microglia were first increased at 3 days; ED1+ and CD11b+ cells were first increased in the middle and upper tract and superior colliculus 7 days post-injury. Increased fibrinogen immunoreactivity indicative of altered BBB permeability was first observed in the contralateral upper tract at 3 days and middle tract at 7 days post-injury. Multiplex cytokine analysis of brain homogenates indicated significant increases in the pro-inflammatory cytokines, IL-2 and TNFa, and anti-inflammatory cytokine IL-10 1 day post-injury, decreasing to control levels at 3 days for TNFa and 7 days for IL-2. IL-10 was significantly elevated at 1 and 7 days post-injury with a dip at 3 days post-injury. Conclusions: Partial injury to the optic nerve induces a complex remote inflammatory response, characterized by rapidly increased pro- and anti-inflammatory cytokines in brain homogenates, increased numbers of IBA1+ cells throughout the visual pathways, and increased CD11b+ and ED1+ inflammatory cells, particularly towards the synaptic terminals. BBB permeability can increase prior to inflammatory cell infiltration, dependent on the brain region

Identification and manipulation of tumor associated macrophages in human cancers

Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed

Controlling emerging infectious diseases in salmon aquaculture

In this paper, the authors review the impacts of diseases facing salmon aquaculture, drawing lessons from terrestrial animal diseases. They discuss the implementation of current control strategies, taking into account transmission patterns (vertical versus horizontal), disease reservoirs, and interactions with wild fish. In addition, the decision-making context of aquatic disease control and the institutional organisation of control strategies are considered, with particular emphasis on the roles and responsibilities of regulatory authorities and the private sector. Case studies on the emergence and control of infectious salmon anaemia worldwide and pancreas disease in Norway are used to examine some of the controversies that may influence decision making and provide lessons for the future

Wide clinical spectrum in ALG8-CDG: clues from molecular findings suggest an explanation for a milder phenotype in the first-described patient

BACKGROUND: Congenital disorders of glycosylation (CDG) includes ALG8 deficiency, a protein N-glycosylation defect with a broad clinical spectrum. If most of the 15 previously reported patients present an early-onset multisystem severe disease and early death, three patients including the cas princeps, present long-term survival and less severe symptoms. METHODS: In order to further characterize ALG8-CDG, two new ALG8 patients are described and mRNA analyses of the ALG8-CDG cas princeps were effected. RESULTS: One new patient exhibited a hepato-intestinal and neurological phenotype with two novel variants (c.91A > C p.Thr31Pro; c.139dup p.Thr47Asnfs*12). The other new patient, homozygous for a known variant (c.845C > T p.Ala282Val), presented a neurological phenotype with epilepsy, intellectual disability and retinis pigmentosa. The cas princeps ALG8-CDG patient was reported to have two heterozygous frameshift variants predicted to be without activity. We now described a novel ALG8 transcript variant in this patient and the 3D model of the putative encoded protein reveals no major difference with that of the normal ALG8 protein. CONCLUSION: The description of the two new ALG8 patients affirms that ALG8-CDG is a severe disease. In the cas princeps, as the originally described frameshift variants are degraded, the novel variant is promoted and could explain a milder phenotype

The Macrophage Transcriptome

Macrophages are specialized but versatile cells that participate in a range of physiological and immune related processes. The macrophage repertoire of coding and regulatory RNA provides tools to understand cell identity, cell function, role in disease, and ultimately define cell specific therapeutic targets. Modern tools make it possible to quantify and compare global RNA levels. With this vast information a neologism of the decade, the suffix “ome” has been combined with “transcript” to form “transcriptome,” a new word to define the totality of transcripts that characterize a cell. In this chapter we discuss the macrophage transcriptome and how its definition is contributing to a deeper understanding of this cell identity and function

Sarcostemma viminale activates macrophages to a pro-inflammatory phenotype

Sarcostemma viminale (L.) R.Br, also known as caustic or milk bush, is a semi-succulent plant commonly found in the North West of Australia. Local Aboriginal populations have long used the milky white sap from this plant to treat skin cancers. An ethanol extract from S. viminale was tested by exposing the RAW264.7 cell line as an in vitro murine macrophage model, to the extract. Flow cytometric analysis was performed to determine if S. viminale skewed macrophages towards a pro-inflammatory or anti-inflammatory phenotype using a number of cell surface markers. Cell culture supernatants were also analysed by cytometric bead array to determine if S. viminale exposed macrophages produced pro-inflammatory or anti-inflammatory cytokines. After exposure to S. viminale, a significantly greater number of macrophages expressed pro-inflammatory major histocompatibility complex (MHC) class II molecules and significantly greater expression levels of the dendritic cell marker CD11c. Cytometric bead array analysis found that S. viminale induced significant amounts of the potent pro-inflammatory cytokine tumour necrosis factor (TNF) from macrophages. The markers CD40 and ICAM-1 were expressed but were not significantly different from the controls. Also, significantly higher expression of CX3CR1 indicated that macrophages were preparing to migrate. No anti-inflammatory cytokines were produced. No significant production of NO2-, IL-6, IFN-? or IL-12 was found. These results demonstrate that S. viminale drives resting macrophages into a pro-inflammatory phenotype, reminiscent of activated immature dendritic cells. If this activation could be achieved in the peri-tumour environment, then S. viminale could be useful as an adjunct therapy for skin cancer. © 2014 Springer-Verlag London