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Table 1 The neurotoxic and neuroprotective properties of inflammatory players after ischemic stroke*

From: The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia

Inflammatory mediators

 

Neurotoxicity

Neuroprotection

Effects of hypothermia

1. Cytokines

IL-1β

Endogenous pyrogen

Promotion gliosis

Increase neurotoxic mediators

Increase Ca2+ in neurons

Edema formation

BBB breakdown

Priming endothelium for leukocyte adherence

Increase survival promoting factors

Induction of IL-1ra

Reduction increased levels

 

TNF-α

Inhibition glutamate uptake

Promotion gliosis

Increase neurotoxic mediators

Increase Ca2+ signaling in neurons

Stimulation apoptosis of endothelial cells

Edema formation

BBB breakdown

Priming endothelium for leukocyte adherence

Increase NF-κB activation

Increase neurotrophic factors

Control extracellular Ca2+

Mediation neuronal plasticity

Activation repair processes of cerebral microvasculature

Induction anti-apoptotic factors

Induction anti-oxidants

Ischemic tolerance induction

Reduction TNF-α levels

Less expression TNF receptor 1

Less NF-κB activation

Reflection:

Varying properties of soluble and membrane-bound form

Region-specific concentration and action

Receptor-specific action

 

IL-6

Endogenous pyrogen

Attraction T lymphocytes

Induction IL-1ra

Reduction IL-6

 

TGF-β

Increase β-amyloid precursor

Increase glial scar formation

Reduction gliosis

Less inflammatory mediators

Suppressed release ROS

Less brain edema

Inhibition neutrophil adherence

Reduction apoptosis

Induction IL-1ra

Promotion angiogenesis

Reflection:

Neuroprotection limited to penumbra

 

IL-10

 

Less release cytokines and expression receptors

Attenuation astrocytic activation

 

2. HMGB Family

HMGB1

Stimulation inflammatory mediators

Activation microglia

Increase NF-κB activation

 

Reduction of brain and plasma HMGB1

Reduction of NF-κB activation

3. Chemokines

CINC, MCP-1, MIP-1, MRF-1, fractalkine

Regulation and migration of leukocyte trafficking

Stimulation BBB permeability

Stimulation phagocytosis

Increase cytokine secretion

Stimulation apoptosis

Scavenge and repair necrotic tissue

Angiogenesis

Downregulation MCP-1

4. Free oxygen radicals

ROS, NO

Lipid peroxidation

Stimulation inflammatory response

Disruption protein biochemistry

 

Suppressed oxidative stress

 

NO

Induction iron loss of cells

Inhibition enzymes DNA replication

Stimulation expression inflammatory mediators

Vasodilator

Reduction nNOS

No influence iNOS

Reflection:

Different response in acute and chronic phase

5. MMPs

MMP-9

(and -2)

BBB breakdown

Stimulation leukocyte adherence and transmigration

Vasogenic edema

Hemorrhagic transformation

Stimulation plasticity, recovery and repair

Clearance necrotic cell debris

Reduction MMP-9

No effect on MMP-2

Reflection:

Contribution to recovery late after injury

Adhesion molecules

    

1. Selectins

E- and P-selectin

Slow down neutrophils and monocytes

Promotion rolling over endothelium

 

Inhibition E-selectin

 

P-selectin

Enhancement platelet binding to neutrophils and monocytes

  
 

L-selectin

Guide unstimulated leukocytes

 

No effect on L-selectin

2. CAMs

ICAM-1and2, VCAM-1

Stronger attachment leukocytes to endothelium

Stimulation diapedesis

  

3. Integrins

LFA-1, Mac-1,

CD11c

Stimulation adhesion to endothelium

Stimulation conformational changes leukocytes for diapedesis

 

No effect on LFA-1

Delayed upregulation of Mac-1 and CD11c

Cellular inflammatory response

    

1. Glia

Microglia

Phagocytosis to clear dead cells

Production inflammatory and cytotoxic mediators

Production neurotrophic factors

Facilitation neurogenesis and plasticity

Less release toxic mediators

Scavenge and removal necrotic debris

Reduction of activation

Reflection:

Different subsets have different roles

 

Astrocytes

Production inflammatory and cytotoxic mediators

Production chemokines

Formation glial scar tissue

Enhancement oxidative stress

Release glutamate

Production neurotrophic factors

Glial scar isolates damaged tissue

 

2. Endothelial cells (BBB)

 

BBB breakdown:

Hyperpermeability to macromolecules

Vasogenic edema

Increase intracranial pressure

Stimulation inflammatory mediators and adhesion molecules

Astrocyte detachment

 

Reduction BBB disruption for large molecules

3. Leukocytes

Neutrophils

Release pro-inflammatory and cytotoxic mediators

Stimulation lipid peroxidation

Release proteolytic enzymes

Damage endothelial cell membrane

Increase BBB permeability

Post-ischemic edema

No-reflow phenomenon

 

Less infiltration

 

Monocytes

Generation superoxide anions

Release pro-inflammatory cytokines

Removal necrotic cell debris and neutrophils

Less infiltration

  1. * See text for references