Abstract
BackgroundInflammation plays a key role in the pathophysiology of ischemic stroke. Some proinflammatory mediators, such as cytokines and chemokines, are produced in stroke. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, displays chemotactic activities in a wide spectrum of leukocytes and plays an important role in brain development. In previous studies, we have found that the expression of CKLF1 increased in rats after focal cerebral ischemia and treatment with the CKLF1 antagonist C19 peptide decreased the infarct size and water content. However, the role of CKLF1 in stroke is still unclear. The objective of the present study was to ascertain the possible roles and mechanism of CKLF1 in ischemic brain injury by applying anti-CKLF1 antibody.MethodsMale Sprague–Dawley rats were subjected to one-hour middle cerebral artery occlusion. Antibody to CKLF1 was applied to the right cerebral ventricle immediately after reperfusion; infarct volume and neurological score were measured at 24 and 72 hours after cerebral ischemia. RT-PCR, Western blotting and ELISA were utilized to characterize the expression of adhesion molecules, inflammatory factors and MAPK signal pathways. Immunohistochemical staining and myeloperoxidase activity was used to determine the extent of neutrophil infiltration.ResultsTreatment with anti-CKLF1 antibody significantly decreased neurological score and infarct volume in a dose-dependent manner at 24 and 72 hours after cerebral ischemia. Administration with anti-CKLF1 antibody lowered the level of inflammatory factors TNF-α, IL-1β, MIP-2 and IL-8, the expression of adhesion molecules ICAM-1 and VCAM-1 in a dose-dependent manner. The results of immunohistochemical staining and detection of MPO activity indicated that anti-CKLF1 antibody inhibited neutrophil infiltration. Further studies suggested MAPK pathways associated with neutrophil infiltration in cerebral ischemia.ConclusionsSelective inhibition of CKLF1 activity significantly protects against ischemia/reperfusion injury by decreasing production of inflammatory mediators and expression of adhesion molecules, thereby reducing neutrophils recruitment to the ischemic area, possibly via inhibiting MAPK pathways. Therefore, CKLF1 may be a novel target for the treatment of stroke.
Highlights
Inflammation plays a key role in the pathophysiology of ischemic stroke
We found that the expression of Chemokine-like factor 1 (CKLF1) increased in rats after focal cerebral ischemia [13]
We found that neutralization of CKLF1 using anti-CKLF1 antibodies protected against focal cerebral ischemia by inhibiting neutrophil infiltration to the ischemic region via mitogen-activated protein kinase (MAPK) pathways in rats
Summary
Inflammation plays a key role in the pathophysiology of ischemic stroke. Some proinflammatory mediators, such as cytokines and chemokines, are produced in stroke. Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Cerebral ischemia triggers a cascade of proinflammatory molecular and cellular events, such as rapid activation of resident cells, infiltration of various types of inflammatory cells into the ischemic brain tissue, and production of proinflammatory mediators, including cytokines and chemokines [1,2,3]. Chemokines belong to a rapidly expanding family of cytokines Their primary function is to control the positioning of cells in tissues and to recruit leukocytes to the site of inflammation [6]. Some studies reported that levels of a variety of chemokines such as monocyte chemoattractant protein-1 (MCP-1) increased in animal models of ischemia and patients with stroke [7,8]
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