Angiotensin II Type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system.
Astrocytes are the major cellular component of the blood-brain barrier glia limitans and act as regulators of leukocyte infiltration via chemokine expression. We have studied angiotensin-II receptor Type 1 (AT1) and related NF-κB signaling in astrocytes. Angiotensin II derives from cleavage of angiotensin I by angiotensin converting enzyme (ACE), angiotensin I deriving from angiotensinogen via cleavage by renin. Level of expression of ACE was slightly increased in transgenic mice that express dominant-negative IκBα in astrocytes (GFAP-IκBα-dn mice), whereas angiotensinogen and renin, also constitutively expressed in the CNS, were unaffected by NF-κB inhibition. Leukocytes infiltrate the hippocampus of mice after unilateral stereotactic lesion of afferent perforant path axons in the entorhinal cortex. Upregulation of the chemokine CXCL10 that normally occurs in response to synaptic degeneration in the dentate gyrus following axonal transection was totally abrogated in GFAP-IκBα-dn mice. Whereas angiotensin II was upregulated in microglia and astrocytes in the dentate gyrus post-lesion, AT1 was exclusively expressed on astrocytes. Blocking AT1 with Candesartan led to significant increase in numbers of infiltrating macrophages in the hippocampus 2days post-lesion. Lesion-induced increases in T-cell infiltration and morphologic glial response were unaffected, and the blood-brain barrier remained intact to horseradish peroxidase. These findings show that angiotensin II signaling to astrocytes via AT1 plays an important role in regulation of leukocyte infiltration to the CNS in response to a neurodegenerative stimulus, and identify potential targets for therapies directed at adaptive immune responses in the CNS.
Füchtbauer
L
L
Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 25, 5000 Odense C, Denmark.
Groth-Rasmussen
M
M
Holm
T H
TH
Løbner
M
M
Toft-Hansen
H
H
Khorooshi
R
R
Owens
T
T
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001812:Blood-Brain Barrier / Q000276:immunology / Q000502:physiology; D001921:Brain / Q000276:immunology* / Q000502:physiology; D054357:Chemokine CXCL10 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology*; D018891:Dentate Gyrus / Q000276:immunology / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D054992:Immunological Synapses / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan