V. Hugh Perry

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 barriers 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.

Microglia in neurodegenerative disease

Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.

Macrophages and microglia in the nervous system

Abstract Why might macrophages be of interest to neurobiologists? Recent evidence shows that macrophages play a role in tissue homeostasis as well as in defence and repair of tissues. We will review here the possible functions of resident and recruited macrophages in the developing and adult nervous system and examine what contribution these cells might make to repair mechanisms in the central and peripheral nervous systems. There is increasing evidence that macrophages form an important component of the non-neuronal cell population in the nervous system and the tools are becoming available that allow us to study these cells in situ.

Systemic infections and inflammation affect chronic neurodegeneration

It is well known that systemic infections cause flare-ups of disease in individuals with asthma and rheumatoid arthritis, and that relapses in multiple sclerosis can often be associated with upper respiratory-tract infections. Here we review evidence to support our hypothesis that in chronic neurodegenerative diseases such as Alzheimers disease, with an ongoing innate immune response in the brain, systemic infections and inflammation can cause acute exacerbations of symptoms and drive the progression of neurodegeneration.

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimers, Parkinsons, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are “primed” to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1β (IL-1β) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1β. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.

Cat and monkey retinal ganglion cells and their visual functional roles

Abstract Retinal ganglion cells, the integrative-output neurons of the retina, can be sorted into functional classes. In the cat, two ganglion cell classes are labelled X and Y. These are distinguished by the different retinal subnetworks that provide their input. X cells are driven by a single linear receptive field center mechanism. Y cells receive center and surround signals and additional signals from nonlinear subunits in their receptive fields. Both X and Y cells are highly sensitive to contrast. X cells project almost exclusively to the A or A1 layers of the lateral geniculate nucleus (LGN). Y cell axons terminate in the A or A1 layers and also the more ventral C layers, and also the superior colliculus. In the monkey, P cells connect the retina to the parvocellular layers of the LGN, have small receptive fields, are wavelength-selective, and are insensitive to contrast. M cells are ganglion cells that send axons to the magnocellular layers of the LGN, are not wavelength-selective, have somewhat larger receptive fields than P cells, and are very sensitive to contrast. Comparisons between cat and monkey ganglion cell classes reveal several important similarities between M cells and X cells.

The ganglion cell and cone distributions in the monkey's retina: implications for central magnification factors.

The distribution of cones and ganglion cells was determined in whole-mounted monkey retinae. Ganglion cell density along the horizontal meridian was asymmetric, being up to three times greater in nasal retina. A similar but smaller asymmetry occurred with cones. The total number of ganglion cells varied from 1.4 to 1.8 X 10(6), agreeing well with counts of optic nerve axons. The variation of ganglion cell density with eccentricity indicates the magnification factor (MF) of the retina. This was compared with MF at the dorsal lateral geniculate nucleus and at striate cortex, revealing that the relative representation of the fovea increases substantially in both thalamus and cortex.

Macrophages and inflammation in the central nervous system

Acute inflammation plays an important role in host tissue defense against injury and infection, and also subsequent tissue repair. In the central nervous system parenchyma, following many types of insults, the acute inflammatory response to rapid neuronal degeneration or challenge with inflammatory substances differs dramatically from that of other tissues. The rapid recruitment of neutrophils is virtually absent and monocytes are only recruited after a delay of several days. It appears that the microenvironment of the central nervous system has evolved mechanisms to protect it from the potentially damaging consequences of some aspects of the acute inflammatory response.

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 Alzheimers disease, Parkinsons 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.

Microglial priming in neurodegenerative disease

Under physiological conditions, the number and function of microglia—the resident macrophages of the CNS—is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state—a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.