Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury
Proinflammatory mediators trigger intensive postischemic inflammatory remodeling of the blood–brain barrier (BBB) including extensive brain endothelial cell surface and junctional complex changes. Junctional adhesion molecule-A (JAM-A) is a component of the brain endothelial junctional complex with...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114000710 |
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| author | Nikola Sladojevic Svetlana M. Stamatovic Richard F. Keep Jamison J. Grailer J. Vidya Sarma Peter A. Ward Anuska V. Andjelkovic |
| author_facet | Nikola Sladojevic Svetlana M. Stamatovic Richard F. Keep Jamison J. Grailer J. Vidya Sarma Peter A. Ward Anuska V. Andjelkovic |
| author_sort | Nikola Sladojevic |
| collection | DOAJ |
| description | Proinflammatory mediators trigger intensive postischemic inflammatory remodeling of the blood–brain barrier (BBB) including extensive brain endothelial cell surface and junctional complex changes. Junctional adhesion molecule-A (JAM-A) is a component of the brain endothelial junctional complex with dual roles: paracellular route occlusion and regulating leukocyte docking and migration. The current study examined the contribution of JAM-A to the regulation of leukocyte (neutrophils and monocytes/macrophages) infiltration and the postischemic inflammatory response in brain ischemia/reperfusion (I/R injury). Brain I/R injury was induced by transient middle cerebral artery occlusion (MCAO) for 30 min in mice followed by reperfusion for 0–5 days, during which time JAM-A antagonist peptide (JAM-Ap) was administered. The peptide, which inhibits JAM-A/leukocyte interaction by blocking the interaction of the C2 domain of JAM-A with LFA on neutrophils and monocytes/macrophages, attenuated I/R-induced neutrophil and monocyte infiltration into brain parenchyma. Consequently, mice treated with JAM-A peptide during reperfusion had reduced expression (~3-fold) of inflammatory mediators in the ischemic penumbra, reduced infarct size (94 ± 39 vs 211 ± 38 mm3) and significantly improved neurological score. BBB hyperpermeability was also reduced. Collectively, these results indicate that JAM-A has a prominent role in regulating leukocyte infiltration after brain I/R injury and could be a new target in limiting post-ischemic inflammation. |
| first_indexed | 2024-12-17T08:34:28Z |
| format | Article |
| id | doaj.art-be26f4c1339244e68041ab1d400ff618 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:34:28Z |
| publishDate | 2014-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-be26f4c1339244e68041ab1d400ff6182022-12-21T21:56:31ZengElsevierNeurobiology of Disease1095-953X2014-07-01675770Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injuryNikola Sladojevic0Svetlana M. Stamatovic1Richard F. Keep2Jamison J. Grailer3J. Vidya Sarma4Peter A. Ward5Anuska V. Andjelkovic6Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding author at: Departments of Pathology and Neurosurgery, University of Michigan, Medical School, 7520A MSRB I, 1150 W Medical Center Dr, Ann Arbor, MI 48109-5602, USA. Fax: +1 734 764 4308.Proinflammatory mediators trigger intensive postischemic inflammatory remodeling of the blood–brain barrier (BBB) including extensive brain endothelial cell surface and junctional complex changes. Junctional adhesion molecule-A (JAM-A) is a component of the brain endothelial junctional complex with dual roles: paracellular route occlusion and regulating leukocyte docking and migration. The current study examined the contribution of JAM-A to the regulation of leukocyte (neutrophils and monocytes/macrophages) infiltration and the postischemic inflammatory response in brain ischemia/reperfusion (I/R injury). Brain I/R injury was induced by transient middle cerebral artery occlusion (MCAO) for 30 min in mice followed by reperfusion for 0–5 days, during which time JAM-A antagonist peptide (JAM-Ap) was administered. The peptide, which inhibits JAM-A/leukocyte interaction by blocking the interaction of the C2 domain of JAM-A with LFA on neutrophils and monocytes/macrophages, attenuated I/R-induced neutrophil and monocyte infiltration into brain parenchyma. Consequently, mice treated with JAM-A peptide during reperfusion had reduced expression (~3-fold) of inflammatory mediators in the ischemic penumbra, reduced infarct size (94 ± 39 vs 211 ± 38 mm3) and significantly improved neurological score. BBB hyperpermeability was also reduced. Collectively, these results indicate that JAM-A has a prominent role in regulating leukocyte infiltration after brain I/R injury and could be a new target in limiting post-ischemic inflammation.http://www.sciencedirect.com/science/article/pii/S0969996114000710Tight junctionsJAM-AStrokeInflammationBlood–brain barrier |
| spellingShingle | Nikola Sladojevic Svetlana M. Stamatovic Richard F. Keep Jamison J. Grailer J. Vidya Sarma Peter A. Ward Anuska V. Andjelkovic Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury Neurobiology of Disease Tight junctions JAM-A Stroke Inflammation Blood–brain barrier |
| title | Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury |
| title_full | Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury |
| title_fullStr | Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury |
| title_full_unstemmed | Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury |
| title_short | Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury |
| title_sort | inhibition of junctional adhesion molecule a lfa interaction attenuates leukocyte trafficking and inflammation in brain ischemia reperfusion injury |
| topic | Tight junctions JAM-A Stroke Inflammation Blood–brain barrier |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114000710 |
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