Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke.
Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, firmly adhered, and transmigrated at sites of endothelial activation in stroke-affected brain areas. The ensuing neutrophil invasion was associated with local blood-brain barrier breakdown and infarct formation. Brain-resident microglia recognized both endothelial damage and neutrophil invasion. In a cooperative manner, they formed cytoplasmic processes to physically shield activated endothelia and trap infiltrating neutrophils. Interestingly, the systemic blockade of very-late-antigen-4 immediately and very effectively inhibited the endothelial interaction and brain entry of neutrophils. This treatment thereby strongly reduced the ischemic tissue injury and effectively protected the mice from stroke-associated behavioral impairment. Behavioral preservation was also equally well achieved with the antibody-mediated depletion of myeloid cells or specifically neutrophils. In contrast, T-cell depletion more effectively reduced the infarct volume without improving the behavioral performance. Thus, neutrophil invasion of the ischemic brain is rapid, massive, and a key mediator of functional impairment, while peripheral T-cells promote brain damage. Acutely depleting T-cells and inhibiting brain infiltration of neutrophils might, therefore, be a powerful early stroke treatment.
Department of Neurology, University of Magdeburg, University Hospital, 39120, Magdeburg, Germany.
Jens
J
Neumann
Monika
M
Riek-Burchardt
Josephine
J
Herz
Thorsten R
TR
Doeppner
Rebecca
R
König
Heiko
H
Hütten
Eloho
E
Etemire
Linda
L
Männ
Anika
A
Klingberg
Thomas
T
Fischer
Michael W
MW
Görtler
Hans-Jochen
HJ
Heinze
Peter
P
Reichardt
Burkhart
B
Schraven
Dirk M
DM
Hermann
Klaus G
KG
Reymann
Matthias
M
Gunzer
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D002545:Brain Ischemia / Q000276:immunology* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D004195:Disease Models, Animal; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D009043:Motor Activity / Q000502:physiology; D020556:Neutrophil Infiltration / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D011897:Random Allocation; D020127:Recovery of Function / Q000502:physiology; D020521:Stroke / Q000276:immunology* / Q000473:pathology
D039041:Integrin alpha4beta1