Review article
The inflammatory response in stroke

https://doi.org/10.1016/j.jneuroim.2006.11.014Get rights and content

Abstract

Recent works in the area of stroke and brain ischemia has demonstrated the significance of the inflammatory response accompanying necrotic brain injury. Acutely, this response appears to contribute to ischemic pathology, and anti-inflammatory strategies have become popular. This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in experimental stroke. It will review the role of specific cell types including leukocytes, endothelium, glia, microglia, the extracellular matrix and neurons. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites will be reviewed as well as the potential for therapy in stroke and hypoxic–ischemic injury.

Introduction

Stroke is one of the most frequent causes of death and disability worldwide, and has significant clinical and socioeconomic impact. Although different mechanisms are involved in the pathogenesis of stroke, there is increasing evidence showing that inflammation accounts for its progression, at least acutely (Barone and Feuerstein, 1999, Chamorro and Hallenbeck, 2006, Samson et al., 2005). A robust inflammatory reaction characterized by peripheral leukocyte influx into the cerebral parenchyma and activation of endogenous microglia follows focal cerebral ischemia (Becker, 1998, Davies et al., 1998, Hallenbeck, 1996, Morioka et al., 1993, Zheng and Yenari, 2004). Cessation of cerebral blood flow leads to energy depletion and necrotic neuron death, which can trigger immune responses ultimately leading to inflammatory cell activation and infiltration. Reperfusion of the occluded vessel, either due to compensation by the collateral circulation, or spontaneous or therapeutic recanalization leads to the generation of reactive oxygen species (ROS) either by reperfusion with oxygenated blood or production within brain and immune cells. ROS can then stimulate ischemic cells, even ischemic neurons, to secrete inflammatory cytokines and chemokines that cause, among other things, adhesion molecule upregulation in the cerebral vasculature and peripheral leukocyte recruitment, respectively. Once activated, inflammatory cells can release a variety of cytotoxic agents including more cytokines, matrix metalloproteinases (MMPs), nitric oxide (NO) and more ROS (Fig. 1). These substances may induce more cell damage as well as disruption of the blood-brain barrier (BBB) and extracellular matrix ((Danton and Dietrich, 2003, Emsley and Tyrrell, 2002). BBB disruption can further potentiate brain tissue injury and contribute to secondary ischemic brain damage by permitting serum elements and blood to enter the brain (Rosenberg, 1999, Siesjo and Siesjo, 1996). Secondary damage develops as a consequence of brain edema, post-ischemic microvascular stasis and vasomotor/hemodynamic deficits leading to hypoperfusion and post-ischemic inflammation, thus involving activation of microglia and brain infiltration of peripheral inflammatory cells (Dirnagl et al., 1999, Siesjo and Siesjo, 1996). This type of migration of peripheral circulating leukocytes into the brain could produce an amplification of inflammatory signal cascades, which will enhance the damage. These processes are especially pronounced during reperfusion when previously occluded vessels are opened and lead to massive influx of ROS and leukocytes into injured brain. Blocking various aspects of the inflammatory cascade has shown to ameliorate injury from experimental stroke (Han and Yenari, 2003), although this has yet to be demonstrated at the clinical level (Becker et al., 2001).

During the past few years, progress has been made towards identifying the roles of important inflammatory signaling molecules, cells and proteins in the process of initiation and development of post-ischemic inflammation. This review focuses on current findings and provides an update on the understanding of post-ischemic inflammation.

Section snippets

Cellular response to ischemic stroke

Inflammation is characterized by the accumulation of inflammatory cells and mediators in the ischemic brain. After ischemia onset, inflammatory cells such as blood-derived leukocytes and microglia are activated and accumulate within the brain tissue subsequently leading to inflammatory injury. Increasing evidence shows that astrocytes may also act as inflammatory cells responding to ischemic stroke.

Adhesion molecules

Adhesion molecules play a pivotal role in the infiltration of leukocytes into the brain parenchyma after stroke and may represent important therapeutic targets (see recent review by (Sughrue et al., 2004). Three major steps, rolling and adhesion and transendothelial migration of leukocytes, are involved in the access of leukocytes to the brain through the endothelial wall. Activated leukocytes, especially neutrophils, result in further damage of ischemic lesions through reperfusion or secondary

Cytokines

Cytokines are upregulated in the brain after a variety of insults including stroke, and are expressed not only in cells of the immune system, but production by resident brain cells, including glia and neurons, have been observed (Liu et al., 1994, Sairanen et al., 2001). The most studied cytokines related to inflammation in stroke are interleukin-1 (IL-1), TNF-α, interleukin-6 (IL-6), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) (Han and Yenari, 2003). Among those cytokines,

Transcriptional regulation of inflammation

It is now well recognized that cerebral ischemia upregulates gene expression. Activation of several transcription factors has been documented in experimental stroke models. Some of these transcription factors are particularly involved in the inflammatory response, and will be discussed here.

Conclusion

Inflammation is increasingly recognized to be the key element in pathological progression of ischemic stroke. Whether inflammation is destructive or beneficial may depend on how severe the ischemia is and the stages of ischemia in which inflammatory responses contribute. Likely, early inflammatory responses may potentiate ischemic injury, while late responses may be important in recovery and repair. Future work should address the optimal timing of inflammation modulating interventions as well

References (212)

  • C.A. Davies et al.

    An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat

    Exp. Neurol.

    (1998)
  • C. Ding et al.

    Diabetes increases expression of ICAM after a brief period of cerebral ischemia

    J. Neuroimmunol.

    (2005)
  • U. Dirnagl et al.

    Pathobiology of ischaemic stroke: an integrated view

    Trends Neurosci.

    (1999)
  • J. El Khoury et al.

    Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease

    Neurobiol. Aging

    (1998)
  • M. Endoh et al.

    Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia

    Brain Res.

    (1994)
  • K. Fassbender et al.

    Proinflammatory cytokines: indicators of infection in high-risk patients

    J. Lab. Clin. Med.

    (1997)
  • K.C. Flanders et al.

    Transforming growth factor-betas in neurodegenerative disease

    Prog. Neurobiol.

    (1998)
  • Q. Gao et al.

    Bone marrow stromal cells increase astrocyte survival via upregulation of phosphoinositide 3-kinase/threonine protein kinase and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and stimulate astrocyte trophic factor gene expression after anaerobic insult

    Neuroscience

    (2005)
  • A. Garau et al.

    Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia

    Cytokine

    (2005)
  • M. Guha et al.

    LPS induction of gene expression in human monocytes

    Cell. Signal.

    (2001)
  • W.D. Hill et al.

    The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia

    Brain Res. Bull.

    (2001)
  • E.A. Irving et al.

    Differential activation of MAPK/ERK and p38/SAPK in neurons and glia following focal cerebral ischaemia in the rat

    Brain Res. Mol. Brain Res.

    (2000)
  • M. Karin et al.

    AP-1 function and regulation

    Curr. Opin. Cell Biol.

    (1997)
  • M.A. Kelly et al.

    Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis

    Exp. Neurol.

    (2006)
  • S.M. Albelda

    Endothelial and epithelial cell adhesion molecules

    Am. J. Respir. Cell Mol. Biol.

    (1991)
  • S.M. Allan et al.

    Cytokines and acute neurodegeneration

    Nat. Rev., Neurosci.

    (2001)
  • M. Asahi et al.

    Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94

    J. Cereb. Blood Flow Metab.

    (2000)
  • M. Asahi et al.

    Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia

    NeuroReport

    (2001)
  • P.A. Baeuerle et al.

    Function and activation of NF-kappa B in the immune system

    Annu. Rev. Immunol.

    (1994)
  • R.F. Bargatze et al.

    Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells

    J. Exp. Med.

    (1994)
  • F.C. Barone et al.

    Inflammatory mediators and stroke: new opportunities for novel therapeutics

    J. Cereb. Blood Flow Metab.

    (1999)
  • F.C. Barone et al.

    Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury

    Stroke

    (1997)
  • M.K. Baskaya et al.

    Protective effect of the 5-lipoxygenase inhibitor AA-861 on cerebral edema after transient ischemia

    J. Neurosurg.

    (1996)
  • A. Basu et al.

    Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury

    J. Cereb. Blood Flow Metab.

    (2005)
  • K.J. Becker

    Inflammation and acute stroke

    Curr. Opin. Neurol.

    (1998)
  • K.J. Becker

    Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke

    Curr. Med. Res. Opin.

    (2002)
  • K. Becker et al.

    Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats

    Stroke

    (2001)
  • A. Blann et al.

    Soluble intercelluar adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1 and von Willebrand factor in stroke

    Blood Coagul. Fibrinolysis

    (1999)
  • J.V. Bonventre et al.

    Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2

    Nature

    (1997)
  • M.P. Bowes et al.

    Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy

    Neurology

    (1995)
  • A.J. Bruce et al.

    Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

    Nat. Med.

    (1996)
  • M. Campanella et al.

    Flow cytometric analysis of inflammatory cells in ischemic rat brain

    Stroke

    (2002)
  • E. Candelario-Jalil et al.

    Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia

    J. Neurochem.

    (2003)
  • A. Cervera et al.

    Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat

    J. Neurosci. Res.

    (2004)
  • A. Chamorro et al.

    The harms and benefits of inflammatory and immune responses in vascular disease

    Stroke

    (2006)
  • P.H. Chan

    Reactive oxygen radicals in signaling and damage in the ischemic brain

    J. Cereb. Blood Flow Metab.

    (2001)
  • H. Chen et al.

    Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat

    Ann. Neurol.

    (1994)
  • Y. Chen et al.

    Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells

    J. Cereb. Blood Flow Metab.

    (2003)
  • Y. Chen et al.

    Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • M. Chopp et al.

    Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain

    J. Cereb. Blood Flow Metab.

    (1996)
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