1,721,120 research outputs found
Stress primes microglia to the presence of systemic inflammation: Implications for environmental influences on the brain
No full textThe macrophage populations of the brain have been well described and include the macrophages of the meninges, the choroid plexus, the perivascular macrophages and the microglia, the resident macrophages of the brain parenchyma. The healthy brain microenvironment has a profound and remarkable impact on microglia and they are well recognised to be a population of macrophages with the most down-regulated or switched off phenotype of all the macrophage populations in the body (Perry and Gordon, 1991). The molecular interactions that regulate the microglia phenotype are beginning to be defined and include CD200 expression on neurons binding CD200R on microglia (Hoek et al., 2000), and neuronal CD22 on neurons binding CD45 on microglia (Mott et al., 2004). The very low or undetectable levels of expression of certain macrophage antigens on microglia, for example, MHC Class II, means that small changes in the levels of expression, or de novo synthesis, are readily detected in experimental models. The rapid changes in morphology and antigen expression has led to the microglia being described as exquisite sensors of even minor pathological change (Kreutzberg, 1996).Communication between the systemic immune system and brain also involves the microglia. Following a systemic inflammatory challenge pro-inflammatory cytokines are synthesised within the brain and there mediate aspects of sickness behaviour. The microglia play a role in the synthesis of these central cytokines (Van Dam et al., 1995). Interestingly it is not only systemic inflammation that can initiate cytokine synthesis in the brain so too can peripheral stressors and recent evidence shows that prior stress leads to an exacerbation of brain cytokine synthesis after a peripheral inflammatory challenge (Johnson et al., 2002), and microglia proliferation (Nair and Bonneau, 2006). As reported in this issue of Brain Behaviour and Immunity Frank et al. (2006) have extended these observations on the interaction between stress and systemic inflammation and show that it is the microglia that are major players in mediating the enhanced cytokine synthesis. In animals that were subjected to inescapable shock the microglia in the CA3 region of hippocampus showed significant upregulation of MHC Class II as detected by immunocytochemisty, and also the levels of CD200 mRNA were reduced. Thus, stress alone is sufficient to activate the microglia and reduce the level of control exerted by the neurons through CD200. Manipulating the degree to which the shock was or was not controlled by the animal appeared not to be an important parameter. Following the period of stress the microglia were then isolated from the hippocampus and challenged ex vivo with lipopolysaccharide (LPS). Microglia from animals that had been subjected to shock were found to synthesise greater amounts of interleukin-1? mRNA than those from control animals challenged with LPS.These interesting studies raise a number of important issues not the least of which is the nature of the pathways and signals that lead from the stressor to the activation of the microglia. The data suggest that the downregulation of CD200 may be important but at the present time we have little idea about the regulation of CD200 expression by neurons. If stress or indeed other systemic events modulate CD200 this will significantly impact on many aspects of neuroimmune communication. Frank et al. also suggest that the astrocytes are not major players but the authors stress that it is likely premature to exclude there cells from the frame. It was notable that the microglia expression of CD11b was not modified by stress and thus any single marker, such as GFAP used to study the astrocyte population, may not be the appropriate or sensitive marker for studying a particular cell type in these conditions. The present study only examined the synthesis of interleukin-1? mRNA and there are clearly many other cytokines and other inflammatory mediators that will be of interest to study.Whatever the mechanisms that underpin how stress leads to the activation of microglia this study adds to a growing body of evidence demonstrating that microglia that may be “primed” (Perry et al., 2003) by a number of different stimuli including neurodegeneration (Cunningham et al., 2005 C. Cunningham, D.C. Wilcockson, S. Campion, K. Lunnon and V.H. Perry, Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration, J. Neurosci. 25 (2005), pp. 9275–9284. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (40)Cunningham et al., 2005), ageing (Godbout et al., 2005) and stress (Johnson et al., 2002) such that a second systemic inflammatory stimulus, e.g., systemic inflammation, may lead to either a switch in phenotype or an exaggerated pro-inflammatory phenotype. This exaggerated cytokine response may lead to acute changes in behaviour or exacerbate pathology. Thus, the microglia are both key sensors of pathology and they also play a critical role in the communication between environmental stressors, systemic pathogens or injury, and toxins, with the brain. It is not hard to see that this will have important consequences for our understanding of environmental influences on mental health and diseases of the brai
Histone H1; a neuronal protein that binds bacterial lipopolysaccharide
No full textBacterial lipopolysaccharide (LPS) is a potent inflammogen following systemic infection. Macrophages express a number of surface molecules including CD14, CD18 and the scavenger receptor that are capable of recognizing and binding LPS. Injection of the CNS with LPS produces an atypical inflammatory response including a delay in the recruitment of macrophages to the brain parenchyma. We have shown using a ligand blot overlay approach, that LPS is capable of binding to histone H1 present in brain homogenate. The ability of LPS to bind to H1 has only been previously shown for monocytes. Subsequent immunohistochemistry revealed that the anti- H1 antibody, ANA-108, stained neuronal cell bodies and was located in the membrane, possibly at the cell surface. Further experiments revealed that the H1 antigen recognized by the ANA-108 antibody was not a histone wholly restricted to the nucleus but may represent a novel CNS form of the protein. This observation has implications for the autoimmune disease systemic lupus erythematosus (SLE) due to the presence of auto-antibodies, particularly against DNA and nuclear proteins, in serum. The formation of immune complexes in various organs leads to severe dysfunction. Anti-histone antibodies are typical of the auto-antibodies found in SLE serum and the presence of the H1 antigen on the surface of neurons could provide an insight into biology underlying the neurological problems associated with SLE.</p
The axon initial segment as a possible determinant of retinal ganglion cell dendritic geometry
No full textIn wholemounted retinae of cat, rat and monkey, in which ganglion cells were retrogradely labelled with horseradish peroxidase, a quantitative analysis of the direction of the axon initial segment with respect to the optic disc and of the relationship between the axon initial segment and the direction and distribution of primary dendrites was performed on the class of largest ganglion cells. The results show the following. (1) In all 3 species, the majority of primary dendrites of ganglion cells are directed away from the axon initial segment. (2) Primary dendrites arise with a greater frequency from the region of the cell body opposite to the axon initial segment than close to it. (3) In cat the direction of the axon initial segments show less variance in their initial direction with respect to the optic disc than in rat or monkey. In adult cats the nucleus of α-ganglion cells occupies a central position. In the kitten the position of the nucleus is eccentric and lies in a part of the cell body opposite to the axon initial segment. The nucleus moves to a central position over the next 3 weeks. The position of the axon initial segment is discussed as a possible determinant of ganglion cell dendritic geometry.</p
Axon pathology in neurological disease: a neglected therapeutic target
No full textIn the C57BL/WldS mouse, a dominant mutation dramatically delays Wallerian degeneration in injury and disease, possibly by influencing multi-ubiquitination. Studies on this mouse show that axons and synapses degenerate by active and regulated mechanisms that are akin to apoptosis. Axon loss contributes to neurological symptoms in disorders as diverse as multiple sclerosis, stroke, traumatic brain and spinal cord injury, peripheral neuropathies and chronic neurodegenerative diseases, but it has been largely neglected in neuroprotective strategies. Defects in axonal transport, myelination or oxygenation could trigger such mechanisms of active axon degeneration. Understanding how these diverse insults might initiate an axon-degeneration process could lead to new therapeutic interventions
Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms
No full textWe have all at some time experienced the non-specific symptoms that arise from being ill following a systemic infection. These symptoms, such as fever, malaise, lethargy and loss of appetite are often referred to as “sickness behavior” and are a consequence of systemically produced pro-inflammatory mediators. These inflammatory mediators signal to the brain, leading to activation of microglial cells, which in turn, signal to neurons to induce adaptive metabolic and behavioral changes. In normal healthy persons this response is a normal part of our defense, to protect us from infection, to maintain homeostasis and causes no damage to neurons. However, in animals and patients with chronic neurodegenerative disease, multiple sclerosis, stroke and even during normal aging, systemic inflammation leads to inflammatory responses in the brain, an exaggeration of clinical symptoms and increased neuronal death. These observations imply that, as the population ages and the number of individuals with CNS disorders increases, relatively common systemic infections and inflammation will become significant risk factors for disease onset or progression. In this review we discuss the underlying mechanisms responsible for sickness behavior induced by systemic inflammation in the healthy brain and how they might be different in individuals with CNS pathology
The topography of magnocellular projecting ganglion cells (M-ganglion cells) in the primate retina
No full textThe projection from the retina to the dorsal lateral geniculate nucleus in the primate arises from two morphologically distinct types of ganglion cells. The P-ganglion cells project to the parvocellular layers, the M-ganglion cells to the magnocellular layers. We have developed a neurofibrillar stain which stains the M-ganglion cell population with a high degree of selectivity allowing us to map their distribution across the retina. As with other ganglion cell types the M-ganglion cell density peaks close to the fovea and declines towards the periphery. At 1 mm from the fovea the proportion of M-ganglion cells ranges from 6 to 10% and then increases to about 8-10% over much of the retina except along the nasal horizontal meridian. Along the nasal horizontal meridian the percentage increases from 10% at 7 mm eccentricity to 20% or more at higher eccentricities. The increased percentage of M-ganglion cells in the nasal quadrant of the retina correlates with the relatively smaller dendritic trees of M-ganglion cells in this region.</p
Microglia in retinae transplanted to the central nervous system
No full textRetinae from fetal rats and mice were transplanted to the brains of neonatal rats: retinae from fetal rats were transplanted to the brains of adult immunodeficient nude mice. Using immunocytochemistry with monoclonal antibodies directed against cell surface antigens on macrophages and lymphocytes, we examined the leukocyte populations in transplants. We have shown that the transplants become populated by macrophages which have the morphology and phenotype of microglia. Furthermore, we have shown that in xenogeneic transplants most, if not all, of these cells are derived from the host. The microglia in the transplant retinae are more numerous and less precisely distributed when compared to normal retinae. Some microglia. particularly those associated with large blood vessels, express antigens typical of reactive microglia. including Class II antigens. We find that large numbers of macrophages and microglia are associated with the outer segments of the photoreceptors. In the absence of the retinal epithelium the macrophages may phagocytose discs shed from the outer segments of rods. We suggest that microglia derived from the host may be an important component of the instability of xenogeneic grafts.</p
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