Role Of Brain Macrophages In Innate Immunity

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Phagocytosis

Macrophages in the CNS have similar functions to those in the periphery. Perivascular macrophages and microglia phagocytose foreign material to limit inflammation and the spread of infection within the brain.4 Microglia also have receptors for apoptotic cells and for an array of proteins such as p-amyloid that accumulate in specific neurodegenerative disease states. As mentioned earlier, ADCC is a process whereby immunoglobulin receptor-bearing microglia/macrophages are brought into proximity with antibody-coated target. Microglia become activated as a result of binding the Fc portion of antibody, as shown by increased NADPH oxidase activity.13 With regard to autoimmune injury, microglia/macrophage attachment to myelin/oligo-dendrocytes with subsequent phagocytosis could be triggered by antibodies directed to antigens expressed on the surface of myelin.14 In MS lesions, expression of all three Fc7 receptor classes is upregulated on microglia cells and macrophages.13 Increased expression of the Fc7 receptors on brain-resident macrophages may be induced by cytokines, particular interleukin-1 (IL-1), IL-6 or tumour necrosis factor alpha (TNF-a). Cytokines also enhance myelin uptake and subsequent breakdown by macrophages and microglia.15 Astrocyte-conditioned medium increases the phagocytosis of myelin by both microglia and macrophages three-fold, suggesting that, in the CNS environment, phagocytosis is a natural occurrence.16 Therefore, it is possible that a typically protective immune response, such as phagocytosis, once misdirected can result in harm to the host.

Secretion of inflammatory molecules

TNF-a is a proinflammatory cytokine produced in large quantities by activated macrophages and microglia in response to various stimuli such as bacterial lipopolysaccharide products. However, members of the adaptive immune response, specifically activated human T-cells, have also been shown to induce microglia production of TNF-a.17,18 TNF-a has been identified in MS plaques,19 and elevated levels of TNF have been found in serum and cerebrospinal fluid (CSF) of MS patients. In addition to its immunoregulatory properties, such as enhancing cytokine secretion (IL-12) and activation of other cell types (natural killer (NK) cells), TNF-a can influence lymphocyte trafficking across endothelium by upregulating the expression of various adhesion molecules.20 Thus the activation of microglia in response to an infectious stimulus may initiate a cascade of events which lead to the recruitment of T-cells into the CNS. These activated T-cells further enhance the activation of microglia. The activated microglia are then able to secrete a variety of mediators, some of which may be neurotoxins that damage oligodendrocytes and myelin, and eventually result in altered neuronal function by either axonal degeneration or other indirect effects as described in the following section.

TNF-a itself may act as a neurotoxin. Intravitreal injection of TNF-a has been shown to induce demyelination of mouse optic nerve axons.21 Similarly, injection into mouse spinal cord causes an EAE-like response.22 In passive transfer EAE, TNF antagonists inhibit the development or severity of disease.23 These observations may be the result of either direct or indirect functions of TNF. In vitro, TNF-a causes demyelination and death of oligoden-drocytes.24 TNF-a does not cause lysis of the cells, but rather induces apoptosis of the oligodendro-cytes. Human oligodendrocytes demonstrate TNF receptor 1 (TNFR1) expression in vitro.25 TNFR1 has a death domain that is responsible for the induction of apoptosis.26 Human oligodendrocytes in vitro are susceptible to high doses of TNF-a over long periods of time (5-7 days).27,28 The concentrations of TNF-a required to mediate neurodegeneration are higher than one would expect to be present in brain, except perhaps in microenvironments immediately surrounding microglia. Cell-bound TNF may be more efficient than soluble TNF-a in mediating oligodendrocyte killing.29 The mechanism by which TNF signals for apoptosis has not been delineated. It is known that TNF-a signals for increased levels of p53,30 a well-characterized inducer of apoptosis. Besides p53 induction, TNF-a increases the expression of CD95 (fas) on the surface of oligodendrocytes as well as the ligand (CD95L) on the surface of effector cells. Oligodendrocytes are sensitive to CD95-mediated apoptosis.31

TNF-a can also contribute to neurotoxicity by increasing the activity of phospholipase A2, which in turn cleaves phosphoglycerocholine to release platelet activating factor (PAF) and arachidonic acid.32 Arachidonic acid may activate NMDA receptors in neurons, which leads to calcium influx and neuronal death.33 Arachidonic acid metabolites may also impair the transport of glutamate in astrocytes, which is an important mechanism for the preservation of neuronal function.34 Neurotoxicity has been attributed to increased extracellular glutamate.

Oligodendrocytes have only the AMPA/kainate type of excitatory glutamate receptor and are highly sensitive to glutamate excitotoxicity.35 In passive transfer EAE, the addition of an AMPA/kainate antagonist reduced the neurological impairment of the recipient mice. Oligodendrocyte loss was reduced in the treated animals, but there was no observed effect on the inflammatory response associated with EAE. These observations would suggest that glutamate excitotoxicity mediated by AMPA/kainate receptors is important in CNS damage in EAE and possibly MS.

Quinolinic acid, which is a metabolite of trypto-phan, may act as a NMDA receptor agonist to induce cell death.36 Quinolinic acid is known to be produced by macrophages and may be one of the more important neurotoxins. Its neurotoxicity can be demonstrated not only under acute conditions, but also with chronic exposure at relatively low concentrations, which may be more relevant for a chronic disease.

Activated macrophages and microglia generate reactive oxygen species (ROS) that may also induce injury of myelin, oligodendrocytes and neurons. Contact between neurons and brain macrophages triggers production of superoxide anion and hydrogen peroxide by macrophages, which leads to neuronal death.37 Nitric oxide (NO) has been implicated in neurotoxicity in many neurological diseases. Many studies using the murine system have implicated NO as key injury mediator in microglia-induced cytotoxicity to oligodendrocytes. However, unlike production by murine macrophages, which are known to produce large amounts of NO, the production of NO by human macrophages or microglia is controversial. Astrocytes, neurons and endothelial cells appear to be the major source of NO within the human CNS.7

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