The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease

Systemic inflammation is associated with sickness behaviour and signals pass from the blood to the brain via macrophage populations associated with the brain, the perivascular macrophages and the microglia. The amplitude, or gain, of this transduction process is critically dependent on the state of activation of these macrophages. In chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, or prion disease the pathology is associated with a highly atypical inflammatory response, characterised by the activation of the macrophage populations in the brain: the cells are primed. Recent evidence suggests that systemic inflammation may impact on local inflammation in the diseased brain leading to exaggerated synthesis of inflammatory cytokines and other mediators in the brain, which may in turn influence behaviour. These interactions suggest that systemic infections, or indeed any systemic challenge that promotes a systemic inflammatory response, may contribute to the outcome or progression of chronic neurodegenerative disease

Microglia activation in acute and chronic neurodegeneration and the impact of systemic infection

Microglia in the normal brain parenchyma are characterized by their downregulated or quiescent state. However, following almost any pathological insult to the brain they become activated and alter their morphology and upregulate their cell surface antigen expression. We have investigated the cytokine profile associated with acute and chronic neurodegeneration and microglia activation. We have shown that following acute injury to the brain, there is a period (24 h) of pro-inflammatory cytokine synthesis, but the microglia are morphologically activated for weeks. In murine prion disease pathology, a model of chronic neurodegeneration, the microglia are significantly increased in number and are morphologically activated. However, the cytokine profile is anti-inflammatory and dominated by TGFb. However, these activated microglia are primed, as a systemic challenge with endotoxin, to mimic a peripheral infection leads to enhanced cytokine synthesis and exaggerated behavioural sequelae. Interactions between systemic inflammation and an ongoing inflammatory response in the brain is relevant to many acute and chronic neurodegenerative conditions in human beings

Microglial physiology: unique stimuli, specialized responses

Microglia, the macrophages of the central nervous system parenchyma, have in the normal healthy brain a distinct phenotype induced by molecules expressed on or secreted by adjacent neurons and astrocytes, and this phenotype is maintained in part by virtue of the blood-brain barrier's exclusion of serum components. Microglia are continually active, their processes palpating and surveying their local microenvironment. The microglia rapidly change their phenotype in response to any disturbance of nervous system homeostasis and are commonly referred to as activated on the basis of the changes in their morphology or expression of cell surface antigens. A wealth of data now demonstrate that the microglia have very diverse effector functions, in line with macrophage populations in other organs. The term activated microglia needs to be qualified to reflect the distinct and very different states of activation-associated effector functions in different disease states. Manipulating the effector functions of microglia has the potential to modify the outcome of diverse neurological diseases

What is immune privilege (not)?

The ‘immune privilege’ of the central nervous system (CNS) is indispensable for damage limitation during inflammation in a sensitive organ with poor regenerative capacity. It is a longstanding notion which, over time, has acquired several misconceptions and a lack of precision in its definition. In this article, we address these issues and re-define CNS immune privilege in the light of recent data. We show how it is far from absolute, and how it varies with age and brain region. Immune privilege in the CNS is often mis-attributed wholly to the blood–brain barrier. We discuss the pivotal role of the specialization of the afferent arm of adaptive immunity in the brain, which results in a lack of cell-mediated antigen drainage to the cervical lymph nodes although soluble drainage to these nodes is well described. It is now increasingly recognized how immune privilege is maintained actively as a result of the immunoregulatory characteristics of the CNS-resident cells and their microenvironment

Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease

Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD), fed exclusively during mouse preimplantation development, leads to offspring with increased weight from birth, sustained hypertension, and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multiligand megalin (LRP2) receptor and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy, with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases

M and P retinal ganglion cells of the owl monkey: morphology, size and photoreceptor convergence

We have estimated photoreceptor convergence to M and P retinal ganglion cells of two closely related nocturnal (owl monkey, Aotus) and diurnal (capuchin monkey, Cebus) anthropoids. Rod convergence is higher in the owl monkey retina while cone convergence to both M and P cells are very similar in the retinas of the owl monkey and the capuchin monkey. These results indicate that during evolution, the owl monkey retina has undergone changes compatible with a more nocturnal lifestyle, but kept a cone to ganglion cell relation similar to that found in diurnal primates