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CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation.
Biochem Biophys Res Commun. 2020 Aug 27; 529(3):839-845.BB

Abstract

Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis with intolerable high motility. SAE is accompanied with brain vascular injury, endothelial hyperpermeability, and neutrophil infiltration into the brain tissue, key inflammatory processes leading to further brain edema and neuronal cell apoptosis. Recent studies from us and others suggest that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is crucial for neutrophil recruitment during SAE. Here we use CXCR2 antagonist SB225002 to characterize the role of CXCR2 in brain infiltration of neutrophil in a murine model of SAE. Systemic administration of high-dose LPS (10 mg/kg) induced evident neutrophil infiltration into the cerebral cortex in wild-type mice. However, CXCR2 antagonist SB225002 markedly attenuated neutrophil infiltration into brain. The CXCR2 expression on neutrophils in the peripheral circulation was dramatically downregulated in response to this LPS dose, and endothelial CXCR2 was significantly upregulated, suggesting endothelial but not neutrophil CXCR2 plays a more important role in neutrophil infiltration into brain. Strikingly, although these CXCR2 antagonist SB225002 treated mice displayed reduced neutrophil infiltration, no change in neutrophil rolling and adhesion was observed. Furthermore, we confirmed that CXCR2 agonist CXCL1 induced a marked increase in actin stress fiber synthesis and paracellular gap formation in cultured cerebral endothelial cells, which is attenuated by SB225002. Thus, these results demonstrate a selective role for endothelial CXCR2 to regulate cerebral vascular permeability and neutrophil transmigration in high-dose LPS induced neuroinflammation, and also suggest a therapeutic potential of CXCR2 antagonist SB225002 in SAE.

Authors+Show Affiliations

Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China.Department of Internal Medicine, University of Arizona, Phoenix, AZ, 85004, USA. Electronic address: twang@email.arizona.edu.Department of Immunology, School of Laboratory Medicine, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, China. Electronic address: qzq7778@bbmc.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32616311

Citation

Wu, Fengjiao, et al. "CXCR2 Antagonist Attenuates Neutrophil Transmigration Into Brain in a Murine Model of LPS Induced Neuroinflammation." Biochemical and Biophysical Research Communications, vol. 529, no. 3, 2020, pp. 839-845.
Wu F, Chen X, Zhai L, et al. CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation. Biochem Biophys Res Commun. 2020;529(3):839-845.
Wu, F., Chen, X., Zhai, L., Wang, H., Sun, M., Song, C., Wang, T., & Qian, Z. (2020). CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation. Biochemical and Biophysical Research Communications, 529(3), 839-845. https://doi.org/10.1016/j.bbrc.2020.05.124
Wu F, et al. CXCR2 Antagonist Attenuates Neutrophil Transmigration Into Brain in a Murine Model of LPS Induced Neuroinflammation. Biochem Biophys Res Commun. 2020 Aug 27;529(3):839-845. PubMed PMID: 32616311.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CXCR2 antagonist attenuates neutrophil transmigration into brain in a murine model of LPS induced neuroinflammation. AU - Wu,Fengjiao, AU - Chen,Xiaofen, AU - Zhai,Liqian, AU - Wang,Hongtao, AU - Sun,Meiqun, AU - Song,Chuanwang, AU - Wang,Ting, AU - Qian,Zhongqing, Y1 - 2020/06/29/ PY - 2020/05/02/received PY - 2020/05/17/accepted PY - 2020/7/4/pubmed PY - 2020/7/4/medline PY - 2020/7/4/entrez KW - CXCR2 KW - Endothelial activation KW - Neuroinflammation KW - Neutrophil migration SP - 839 EP - 845 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 529 IS - 3 N2 - Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis with intolerable high motility. SAE is accompanied with brain vascular injury, endothelial hyperpermeability, and neutrophil infiltration into the brain tissue, key inflammatory processes leading to further brain edema and neuronal cell apoptosis. Recent studies from us and others suggest that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is crucial for neutrophil recruitment during SAE. Here we use CXCR2 antagonist SB225002 to characterize the role of CXCR2 in brain infiltration of neutrophil in a murine model of SAE. Systemic administration of high-dose LPS (10 mg/kg) induced evident neutrophil infiltration into the cerebral cortex in wild-type mice. However, CXCR2 antagonist SB225002 markedly attenuated neutrophil infiltration into brain. The CXCR2 expression on neutrophils in the peripheral circulation was dramatically downregulated in response to this LPS dose, and endothelial CXCR2 was significantly upregulated, suggesting endothelial but not neutrophil CXCR2 plays a more important role in neutrophil infiltration into brain. Strikingly, although these CXCR2 antagonist SB225002 treated mice displayed reduced neutrophil infiltration, no change in neutrophil rolling and adhesion was observed. Furthermore, we confirmed that CXCR2 agonist CXCL1 induced a marked increase in actin stress fiber synthesis and paracellular gap formation in cultured cerebral endothelial cells, which is attenuated by SB225002. Thus, these results demonstrate a selective role for endothelial CXCR2 to regulate cerebral vascular permeability and neutrophil transmigration in high-dose LPS induced neuroinflammation, and also suggest a therapeutic potential of CXCR2 antagonist SB225002 in SAE. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/32616311/CXCR2_antagonist_attenuates_neutrophil_transmigration_into_brain_in_a_murine_model_of_LPS_induced_neuroinflammation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(20)31046-9 DB - PRIME DP - Unbound Medicine ER -
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