Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury

Nikola Sladojevic; Svetlana M. Stamatovic; Richard F. Keep; Jamison J. Grailer; J. Vidya Sarma; Peter A. Ward; Anuska V. Andjelkovic

Neurobiology of Disease (Jul 2014)

Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury

Nikola Sladojevic,
Svetlana M. Stamatovic,
Richard F. Keep,
Jamison J. Grailer,
J. Vidya Sarma,
Peter A. Ward,
Anuska V. Andjelkovic

Affiliations

Nikola Sladojevic: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Svetlana M. Stamatovic: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Richard F. Keep: Department 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, USA
Jamison J. Grailer: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
J. Vidya Sarma: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Peter A. Ward: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Anuska V. Andjelkovic: Department 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.

Journal volume & issue: Vol. 67
pp. 57 – 70

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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