PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Janus Face of Neuroinflammation: Role in Neural Cell Survival and Death by Tahira Farooqui, Ph.D. The brain contains several types of cells such as neurons, astrocytes, oligodendrocytes, and microglial cells. Collectively these cells are called neural cells. Glial cells account for more than 65% of the total cell population in the brain and spinal cord. Glial cells provide key neuromodulatory, neurotrophic, and neuroimmune mediators for the protection, growth and survival of neurons in brain tissue. Glial cells also chaperone neurons to neuronal synaptic sites, maintaining the functional integrity of the synapse and the integrity of extracellular matrix proteins {Kettenmann and Ransom, 2005}. Neural cell membranes are made of phospholipids, sphingolipids, cholesterol and proteins. Phospholipids contain glycerol backbone, fatty acids, phosphoric acid and nitrogenous bases. The proportions of arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) at the sn-2 position of glycerol moiety of phospholipids vary considerably in the various phospholipids {Farooqui and Horrocks, 2007}. Plasmalogens contain high levels of DHA, whereas phosphatidylcholine is enriched in AA. Neuroinflammation is a complex mechanism that protects and isolates uninjured brain tissue from the damaged cells. It destroys injured cells, and restores normal tissue structure and function. Without a strong inflammatory response, brain tissue would be highly susceptible to neurological damage in cases of stroke, spinal cord injury, head injury, Alzheimers disease, Parkinsons disease, Amyotrophic lateral sclerosis, multiple sclerosis, AIDS and microbial, viral, and prion infections. All brain cells (microglia, astrocytes, neurons, and oligodendrocytes) participate in inflammatory responses. The hallmark of neuroinflammation is the activation of microglial cells. These cells represent brain macrophages. In a normal brain, microglial cells have ramified morphology and are called resting microglia. They represent 20% of the total glial cell population {Kettenmann and Ransom, 2005}. Following brain injury or infection the resting microglia are activated and transformed into activated microglia. The activated microglia have ameboid morphology. The activated microglia migrate rapidly to the injury site, phagocytose dead cells, and clear cellular debris {Farooqui and Horrocks, 2007}. Microglial cell activation is followed by the recruitment of polymorphonuclear leukocytes (PMN) from the blood stream into brain tissue. This PMN migration is a coordinated multistep process involving chemotaxis (adhesion of PMN to endothelial cells in the area of inflammation), and diapedesis (penetration of tight junctions and migration through the endothelial monolayer and into the interstitium) {Diamond, et al 1999}. These PMN eliminate invading antigens by phagocytosis and release free radicals and lytic enzymes into phagolysosomes. This is followed by a process called resolution, a turning-off mechanism utilized by neural cells to limit tissue injury. Many inflammatory reactions resolve spontaneously, but overwhelming chronic, as well as acute, inflammations lead to brain damage {Serhan, 2006}. The chemical nature of signals that initiate the activation of microglial cell response to cell brain injury or infection remains unknown. However, it is suggested that alterations in ion homeostasis, acid base balance and generation of lipid mediators may play an important role in microglial cell activation, initiation, and maintenance of inflammatory response. Neurochemically, inflammatory response requires the generation of proinflammatory lipid mediators such as eicosanoids and platelet activating factor from neural membrane phospholipids {Farooqui and Horrocks, 2007}. Injury-mediated stimulation of phospholipase A2 (PLA2) results in generation of AA and lysophospholipid. AA is oxidized to a variety of proinflammatory and anti-inflammatory lipid mediators including prostaglandins, leukotrienes, thromboxanes, and lipoxins through the action of cyclooxygenases (COX) and lipoxygenases (LOX). These mediators are collectively called eicisanoids. Eicosanoids are unique in the sense that they can cross the cell membrane and leave the cell in which they are generated to act on neighboring cells because of their amphiphilic nature. Some eicosanoids are proinflammatory while others are anti-inflammatory. Oxidation of arachidonic acid also generates reactive oxygen species (ROS). ROS include oxygen radical, superoxide radical, hydroxyl radical, alkoxyl and peroxyl radicals {Farooqui and Horrocks, 2007}. Lysophospholipid, the other product of the PLA2 catalyzed reaction, is acetylated to proinflammatory mediators called platelet activating factor (PAF). During inflammatory reaction eicosanoids not only initiate inflammatory responses, but also mediate resolution. There are two phases in inflammatory responses: one at the onset for the generation of proinflammatory eicosanoids and the other at resolution for the synthesis of pro-resolving eicosanoids {Gilroy et al 2004}. The first phase of arachidonic acid formation involves the expression and stimulation of iPLA2 with the generation of PGE2, LTB4, and PAF through COX-2, LOX, and acetyl-CoA acetyltransferase reactions, respectively. The second phase of arachidonic acid release utilizes sPLA2 as well as cPLA2 and is associated with the generation of PAF, lipoxins, and the pro-resolving prostaglandin, PGD2 {Gilroy, et al 2004}. Thus, eicosanoids (prostaglandins) not only serve as autocrine factors regulating platelet aggregation, vascular tone, and edema, but are also involved in resolution of inflammation by lipoxins. In response to neuroinflammation, microglial and astroglial cells also secrete immune modulators called cytokines {Rothwell, 1999}. Cytokines include interleukin-1 alpha (IL-1?), interleukin-1 beta (IL-1?), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-18 (IL-18), tumor necrosis factor-alpha (TNF-?), colony-stimulating factor-1, and tumor and growth factors (TGF- ? and ?). The released cytokines act through their receptors causing activation of cascades of protein kinases and the pathway leading to activation of the transcription factor nuclear factor kappa B (NF-?B). Activated NF-?B migrates to the nucleus where it mediates the transcription of many genes implicated in inflammatory and immune responses {Farooqui and Horrocks, 2007}. These genes include COX-2, intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, TNF-?, IL-1?, IL-6, sPLA2, inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Its activation also leads to the local generation of more cytokines, which in turn promotes inflammatory signals. Cytokines also stimulate PLA2, COX, and LOX, causing the release of more AA from neural membrane phospholipids and generates more lysophospholipids, eicosanoids, PAF, and ROS. This endogenous mechanism of enrichment of proinflammatory metabolites is called as positive feed-forward loop. It amplifies cytokine-mediated generation of AA metabolites in the brain and spinal cord tissues {Rothwell, 1999}. Action of plasmalogen-selective PLA2 on plasmalogen releases DHA. DHA is metabolized by 15-lipoxygenase-like enzyme to 17S-resolvins, 10-,17S-docosatrienes, and protectins {Marcheselli, et al 2003. Serhan, 2006}. These second messengers have the collective name of docosanoids. They are potent, endogenous, anti-inflammatory and pro-resolving chemical lipid mediators {Serhan, 2006}. They antagonize the effects of eicosanoids, modulate leukocyte trafficking, and down-regulate the expression of cytokines in glial cells. The specific receptors for these bioactive lipid metabolites occur in neural and non-neural tissues. These receptors include resolvin D receptors (resoDR1), resolvin E receptors (resoER1), and neuroprotectin D receptors (NPDR). Characterization of these receptors in brain tissue is in progress {Marcheselli, 2003; Serhan, 2006}. Collectively these studies suggest that the modulation of eicosanoid and docosanoid receptors by different dietary fatty acids may contribute to the regulation of acute and chronic inflammatory processes. Thus, a moderate intake of AA and its precursors and the appropriate ratio between AA and DHA may play an important role in physiologic functioning of the immune system, and in modulation of inflammation in brain tissue. Very little is known about the optimal AA to DHA ratio in diet for the immunologic response against pathogens that can be effective in treating neuroinflammation; more studies are urgently required on this important topic. References Diamond, P., McGinty, A., Sugrue, D., Brady, H.R., Godson, C. (1999) Regulation of leukocyte trafficking by lipoxins. Clin Chem Lab Med. 37: 293-297. Farooqui, A.A. and Horrocks, L.A. (2007) Glycerophospholipids in the Brain: Phospho- lipases A2 in Neurological Disorders, Springer, New York. Gilroy, D.W., Newson, J., Sawmynaden, P.A., Willoughby, D.A. and Croxtall, J.D. (2004) A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J. 18: 489-498. Kettenmann, H. and Ransom, B.R. (2005) Neuroglia, Kettenmann, H. and Ransom, B.R. (eds), 2nd edition, Oxford University Press, New York. Marcheselli V. L., Hong S., Lukiw W. J., Tian X. H., Gronert K., Musto A., Hardy M., Gimenez J. M., Chiang N., Serhan C. N., and Bazan N. G. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807-43817. Rothwell N. J. (1999) Annual review prize lecture cytokines - killers in the brain? J. Physiol. (London) 514, 3-17. Serhan C. N. (2006) Novel chemical mediators in the resolution of inflammation: Resolvins and protectins. Anesthesiol. Clinics North Am. 24, 341-VII. Yeo J. F., Ong W. Y., Ling S. F., and Farooqui A. A. (2004) Intracerebroventricular injection of phospholipases A2 inhibitors modulates allodynia after facial carrageenan injection in mice. Pain 112, 148-155. ### << Previous Next >> [ View All Perspectives ] |
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