Abstract
BackgroundN-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemokine produced through the proteolytic destruction of collagen by matrix metalloproteinases (MMPs). While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated.FindingsWe examined the effects of ac-PGP on primary cortical neurons and found that it binds neuronal CXCR2 receptors, activates extracellular signal-regulated kinase 1/2 (ERK1/2), and induces apoptosis associated with caspase-3 cleavage in a dose-dependent manner. After transient ischemic stroke in rats, ac-PGP was significantly upregulated in infarcted brain tissue.ConclusionsThe production of ac-PGP in brain in ischemia/reperfusion injury and its propensity to induce apoptosis in neurons may link MMP-mediated destruction of the extracellular matrix and opening of the blood-brain barrier to progressive neurodegeneration associated with the initiation and propagation of inflammation. Ac-PGP may be a novel neurotoxic inflammatory mediator involved in sustained inflammation and neurodegeneration in stroke and other neurological disorders associated with activation of MMPs.
Highlights
Chemokines and chemoattractant peptides direct leukocytes to sites of inflammation
The production of acetyl proline-glycine-proline (ac-PGP) in brain in ischemia/reperfusion injury and its propensity to induce apoptosis in neurons may link matrix metalloproteinase (MMP)-mediated destruction of the extracellular matrix and opening of the blood-brain barrier to progressive neurodegeneration associated with the initiation and propagation of inflammation
Ac-PGP may be a novel neurotoxic inflammatory mediator involved in sustained inflammation and neurodegeneration in stroke and other neurological disorders associated with activation of MMPs
Summary
Chemokines and chemoattractant peptides direct leukocytes to sites of inflammation. The CXCR2 chemokine receptor is the primary receptor mediating neutrophil chemotaxis, and CXCR2 and its ligands, CXCL1 (growthrelated oncogene α (GRO-α)), CXCL2 (growth-related oncogene β (GRO-β)), and CXCL8 (interleukin-8 (IL-8)) are implicated in injury processes in stroke and other neurological disorders. CXCR2-mediated infiltration of neutrophils into reperfused tissue has been demonstrated to be a primary mediator of tissue injury in numerous ischemia/reperfusion models, including ischemic stroke [4], and neuroprotection associated with CXCR2 receptor blockade has been presumed to occur largely indirectly through attenuation of leukocyte migration and activation. Degradation of the extracellular matrix (ECM) by MMPs facilitates opening of the blood-brain barrier and promotes hemorrhagic transformation and infiltration of inflammatory cells to the ischemic site [9]. While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated
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