ABSTRACT
Title
Understanding the dual role of the neuroinflammatory response to stroke for validation of novel therapeutic targets
Authors
1D. Amantea, 1G. Bagetta and 2M.T. Corasaniti
1Dept. of Pharmacobiology and UCADH Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity (http://gbagetta.jimdo.com), University of Calabria, Rende (CS), Italy
2Dept. of Phamacobiological Sciences, “Magna Graecia” University, Catanzaro, Italy
1Dept. of Pharmacobiology and UCADH Section of Neuropharmacology of Normal and Pathological Neuronal Plasticity (http://gbagetta.jimdo.com), University of Calabria, Rende (CS), Italy
2Dept. of Phamacobiological Sciences, “Magna Graecia” University, Catanzaro, Italy
Abstract
Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells accumulate in the capillaries to further impair cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, release pro-inflammatory mediators, such as cytokines, chemokines and oxygen/nitrogen free radicals that contribute to the evolution of tissue damage. Matrix metalloproteinases (MMPs) are involved in the propagation and regulation of the neuroinflammatory response to ischemic brain injury[1] cleaving protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also processing a number of cell surface and soluble proteins including receptors and cytokines, such as interleukin(IL)-1beta [2,3]. The latter plays a pivotal role on the evolution of ischemic brain damage [4], showing a specific cellular and regional pattern of expression depending on the progression of ischemia-reperfusion injury. In fact, early astrocytic expression of this cytokine is seen in the penumbra, and a late microglia/macrophages expression is observed throughout the ispilateral brain hemisphere of rats subjected to transient middle cerebral artery occlusion [5].
Interestingly, cytokines (e.g. IL-6), growth factors and hormones (e.g., estradiol, leptin), that play a protective role in the course of cerebral ischemia, use the transcription factor Signal Transducer and Activator of Transcription (STAT)-3 to promote upregulation of neuroprotective and neurotrophic genes, such as bcl-2, bcl-xL, and suppressors of cytokine signalling (SOCS). By western blotting and immunofluorescence analysis, we have observed a time-and region-specific activation (tyrosine phosphorylation) of STAT3 in the ischemic brain, being this mediator expressed in astrocytes of the peri-ischemic cortex during the early stages after the insult, and in neurons and microglial cells of the ispilateral hemisphere at later times. STAT3 activation in astrocytes may indirectly be linked to neuronal survival, whereas its activation in microglia/macrophages may contribute to the detrimental neuroinflammatory response to tissue injury by inducing the expression of proinflammatory cytokines such as IL-1beta and TNF-alfa. Therefore, STAT-3 represents a crucial link between the neuroinflammatory response and the neurodegeneration/neurorepair mechanisms occurring in the ischemic brain.
Thus, the dual role of neuroinflammatory mediators on the evolution of ischemic brain damage suggests that time- and mechanism-specific pharmacological targeting should be strongly considered for the development of novel effective therapeutics.
[1] Amantea et al. (2008) Neurosci 152, 8-17.
[2] Sternlicht and Werb (2001) Annu Rev Cell Dev Biol 17, 463-516.
[3] Amantea et al. (2007) Int Rev Neurobiol 82, 149-69.
[4] Allan et al. (2005) Nat Rev Immunol 5, 629-40.
[5] Amantea et al. (2010) Brain Res 1313, 259-69.
Financial support from the Italian Ministry of University and Research (PRIN prot. 20089BARSR_004) and from the Ministry of Health (Ricerca Finalizzata 2005, Conv. n. 105, Titolo del progetto: “Meccanismi di protezione e danno neuronale nella deprivazione energetica”) is gratefully acknowledged
Interestingly, cytokines (e.g. IL-6), growth factors and hormones (e.g., estradiol, leptin), that play a protective role in the course of cerebral ischemia, use the transcription factor Signal Transducer and Activator of Transcription (STAT)-3 to promote upregulation of neuroprotective and neurotrophic genes, such as bcl-2, bcl-xL, and suppressors of cytokine signalling (SOCS). By western blotting and immunofluorescence analysis, we have observed a time-and region-specific activation (tyrosine phosphorylation) of STAT3 in the ischemic brain, being this mediator expressed in astrocytes of the peri-ischemic cortex during the early stages after the insult, and in neurons and microglial cells of the ispilateral hemisphere at later times. STAT3 activation in astrocytes may indirectly be linked to neuronal survival, whereas its activation in microglia/macrophages may contribute to the detrimental neuroinflammatory response to tissue injury by inducing the expression of proinflammatory cytokines such as IL-1beta and TNF-alfa. Therefore, STAT-3 represents a crucial link between the neuroinflammatory response and the neurodegeneration/neurorepair mechanisms occurring in the ischemic brain.
Thus, the dual role of neuroinflammatory mediators on the evolution of ischemic brain damage suggests that time- and mechanism-specific pharmacological targeting should be strongly considered for the development of novel effective therapeutics.
[1] Amantea et al. (2008) Neurosci 152, 8-17.
[2] Sternlicht and Werb (2001) Annu Rev Cell Dev Biol 17, 463-516.
[3] Amantea et al. (2007) Int Rev Neurobiol 82, 149-69.
[4] Allan et al. (2005) Nat Rev Immunol 5, 629-40.
[5] Amantea et al. (2010) Brain Res 1313, 259-69.
Financial support from the Italian Ministry of University and Research (PRIN prot. 20089BARSR_004) and from the Ministry of Health (Ricerca Finalizzata 2005, Conv. n. 105, Titolo del progetto: “Meccanismi di protezione e danno neuronale nella deprivazione energetica”) is gratefully acknowledged