/pdf/inflammation-as-a-central-mechanism-in-alzheimer-s-disease-eiiqrx1far.pdf

Inflammation as a central mechanism in Alzheimer's disease

Biology of interleukin-10

Influenza viruses are a major pathogen of both humans and animals. Recent studies using gene-knockout mice have led to an in-depth understanding of the innate sensors that detect influenza virus infection in a variety of cell types. Signalling downstream of these sensors induces distinct sets of effector mechanisms that block virus replication and promote viral clearance by inducing innate and adaptive immune responses. In this Review, we discuss the various ways in which the innate immune system uses pattern recognition receptors to detect and respond to influenza virus infection. We consider whether the outcome of innate sensor stimulation promotes antiviral resistance or disease tolerance, and propose rational treatment strategies for the acute respiratory disease that is caused by influenza virus infection.

/pdf/innate-immunity-to-influenza-virus-infection-4nlbgchrmb.pdf

Innate immunity to influenza virus infection.

The journal of pharmacology and experimental therapeutics

Viral pathogens often induce strong effector CD4(+) T cell responses that are best known for their ability to help B cell and CD8(+) T cell responses. However, recent studies have uncovered additional roles for CD4(+) T cells, some of which are independent of other lymphocytes, and have described previously unappreciated functions for memory CD4(+) T cells in immunity to viruses. Here, we review the full range of antiviral functions of CD4(+) T cells, discussing the activities of these cells in helping other lymphocytes and in inducing innate immune responses, as well as their direct antiviral roles. We suggest that all of these functions of CD4(+) T cells are integrated to provide highly effective immune protection against viral pathogens.

/pdf/expanding-roles-for-cd4-t-cells-in-immunity-to-viruses-187j0y18re.pdf

Expanding roles for CD4 + T cells in immunity to viruses

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer’s disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition.

/pdf/non-alcoholic-fatty-liver-disease-induces-signs-of-alzheimer-4unc5l83ki.pdf

Non-alcoholic Fatty Liver Disease Induces Signs of Alzheimer's Disease (AD) in Wild-Type Mice and Accelerates Pathological Signs of AD in an AD Model

Microglia are active players in inflammation, but also have important supporting roles in CNS maintenance and function, including modulation of neuronal activity We previously observed an increase in the frequency of excitatory postsynaptic current in organotypic brain slices after depletion of microglia using clodronate Here, we describe that local hippocampal depletion of microglia by clodronate alters performance in tests of spatial memory and sociability Global depletion of microglia by high-dose oral administration of a Csf1R inhibitor transiently altered spatial memory but produced no change in sociability behavior Microglia depletion and behavior effects were both reversible, consistent with a dynamic role for microglia in the regulation of such behaviors

Dynamic microglial modulation of spatial learning and social behavior.

Interleukin-10 (IL-10) is known to play a critical immunoregulatory role during immune responses to microbial pathogens. Many bacterial and viral infections stimulate host IL-10 production, which is ultimately beneficial or detrimental, depending upon the type of infection. In animal models, IL-10 production by dendritic cells is proposed to be critical for the induction of tolerance that is induced by respiratory exposure to antigen (2). During the host defense against microbial infection, IL-10 can hamper pathogen clearance but can also improve immunopathology by regulating innate and adaptive immunity and limiting the magnitude of inflammatory responses. IL-10 can enhance chronic infections caused by Leishmania and lymphocytic choriomeningitis virus (LCMV) due to the suppression of immune responses to these pathogens (1, 3, 4, 8). On the other hand, IL-10 was shown to inhibit immunopathological consequences following infection with a wide variety of pathogens, including Toxoplasma gondii, Trypanosoma cruzi, and Helicobacter hepaticus (20).

With chronic viral infections, IL-10 can enhance microbial persistence through the induction of immunological anergy (13). Specifically, during LCMV infection of mice, IL-10 is responsible for the functional impairment and deletion of virus-specific CD8+ T cells as well as a more general immunosuppression (3, 4, 8). On the other hand, information regarding the role of IL-10 during acute influenza virus infection appears to be contradictory. Sun et al. (17) previously found that an inhibition of IL-10 signaling in the midst of an ongoing influenza virus infection resulted in increased inflammation and decreased survival. However, the influence of IL-10 during the early stages of immune response induction after viral infection was not examined. Conversely, a recent study by McKinstry et al. (14) reported that IL-10-deficient mice have significantly increased survival after influenza infection. Conclusions regarding the beneficial or detrimental role of IL-10 in these two studies were based entirely on survival studies, but no significant influence of IL-10 on viral persistence or clearance was reported.

Previously, we used C57BL/6 IL-10−/− mice to investigate the role of IL-10 during post-influenza virus bacterial infection (18). In those experiments, mice were first intranasally (i.n.) challenged with a sublethal dose (10 PFU) of influenza virus, followed approximately 1 week later with i.n. Streptococcus pneumoniae challenge. Compared to wild-type (WT) mice, IL-10−/− mice did not have notably improved survival from secondary bacterial infection in this coinfection model. Remarkably, however, IL-10−/− mice had a significantly decreased viral burden at the recovery stage of sublethal influenza virus infection (18). To our knowledge, this was the first evidence that IL-10 actually influenced the kinetics of viral clearance during acute influenza infection. Importantly, the use of viral burden as a readout provided a tremendous advantage for studying the underlying immune mechanisms responsible for microbial synergy while minimizing the nonspecific effects of a lethal viral burden. We have now used IL-10−/− mice to further investigate the regulatory role of IL-10 and have found that IL-10 has a detrimental role during initial responses to primary influenza virus infection regardless of the challenge dose. Our results indicate that IL-10 inhibits CD4+ T-cell-helper function during the induction of initial virus-specific antibody responses and thereby leads to impaired resistance to primary influenza virus infection.

A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection.

Spinal cord injury (SCI) causes permanent debilitation due to the inability of axons to grow through established scars. Both the sugar chains and core proteins of chondroitin sulfate proteoglycans (CSPGs) are inhibitory for neurite regrowth. Chondroitinase ABC (ChABC) degrades the sugar chains and allows for synaptic plasticity, suggesting that after the sugar chain cleavage additional steps occur promoting a permissive microenvironment in the glial scar region. We report that the clearance of the core protein by the tissue plasminogen activator (tPA)/plasmin proteolytic system partially contributes to ChABC-promoted plasticity. tPA and plasmin are upregulated after SCI and degrade the deglycosylated CSPG proteins. Mice lacking tPA (tPA(-/-)) exhibit attenuated neurite outgrowth and blunted sensory and motor recovery despite ChABC treatment. Coadministration of ChABC and plasmin enhanced the tPA(-/-) phenotype and supported recovery in WT SCI mice. Collectively, these findings show that the tPA/plasmin cascade may act downstream of ChABC to allow for synergistic sensory and motor improvement compared with each treatment alone and suggest a potential new approach to enhance functional recovery after SCI.

https://www.jneurosci.org/content/jneuro/31/42/14931.full.pdf

Axonal Regrowth after Spinal Cord Injury via Chondroitinase and the Tissue Plasminogen Activator (tPA)/Plasmin System

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with cognitive decline and complete loss of basic functions. The ubiquitous apicomplexan parasite Toxoplasma gondii (T. gondii) infects up to one third of the world’s population and is implicated in AD. We infected C57BL/6 wild-type male and female mice with 10 T. gondii ME49 cysts and assessed whether infection led to behavioral and anatomical effects using immunohistochemistry, immunofluorescence, Western blotting, cell culture assays, as well as an array of mouse behavior tests. We show that T. gondii infection induced two major hallmarks of AD in the brains of C57BL/6 male and female mice: beta-amyloid (Aβ) immunoreactivity and hyperphosphorylated Tau. Infected mice showed significant neuronal death, loss of N-methyl-d-aspartate receptor (NMDAR) expression, and loss of olfactory sensory neurons. T. gondii infection also caused anxiety-like behavior, altered recognition of social novelty, altered spatial memory, and reduced olfactory sensitivity. This last finding was exclusive to male mice, as infected females showed intact olfactory sensitivity. These results demonstrate that T. gondii can induce advanced signs of AD in wild-type mice and that it may induce AD in some individuals with underlying health problems.

/pdf/toxoplasma-gondii-alters-nmdar-signaling-and-induces-signs-iacb7cnnwj.pdf

Luisa Torres

Papers

Non-alcoholic Fatty Liver Disease Induces Signs of Alzheimer's Disease (AD) in Wild-Type Mice and Accelerates Pathological Signs of AD in an AD Model

Dynamic microglial modulation of spatial learning and social behavior.

A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection.

Axonal Regrowth after Spinal Cord Injury via Chondroitinase and the Tissue Plasminogen Activator (tPA)/Plasmin System

Toxoplasma gondii alters NMDAR signaling and induces signs of Alzheimer’s disease in wild-type, C57BL/6 mice