Innate immune-mediated neuronal injury consequent to loss of astrocytes.
Neuronal injury and loss are recognized features of neuroinflammatory disorders, including acute and chronic encephalitides and multiple sclerosis; destruction of astrocytes has been demonstrated in cases of Rasmussen encephalitis. Here, we show that innate immune cells (i.e. natural killer [NK] and gammadelta T cells) cause loss of neurons from primary human neuron-enriched cultures by destroying the supporting astrocytes. Interleukin 2-activated NK cells caused loss of astrocytes within 1 hour, whereas neurons were lost at 4 hours. Time-lapse imaging indicated that delayed neuron loss was due to early destruction of supporting astrocytes. Selective blocking of astrocyte death with anti-NKG2D antibodies reduced neuron loss, as did blocking of CD54 on astrocytes. gammadelta T cells also induced astrocyte cytotoxicity, leading to subsequent neuronal displacement. In astrocytes, NK cells caused caspase-dependent fragmentation of the intermediate filament proteins glial fibrillary acidic protein and vimentin, whereas anti-CD3-activated T cells produced fragmentation to a lesser extent and without measurable cytotoxicity. Glial fibrillary acidic protein fragmentation was also demonstrated in lysates from chronic multiple sclerosis plaques but not from normal control white matter. These data suggest that non-major histocompatibility complex-restricted immune effector cells may contribute to neuron loss in neuroinflammatory disorders indirectly through injury of glia.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Peter J
PJ
Darlington
Cornelia
C
Podjaski
Katherine E
KE
Horn
Santiago
S
Costantino
Manon
M
Blain
Philippe
P
Saikali
Zhihong
Z
Chen
Kenneth Adam
KA
Baker
Jia
J
Newcombe
Mark
M
Freedman
Paul W
PW
Wiseman
Amit
A
Bar-Or
Timothy E
TE
Kennedy
Jack P
JP
Antel
D001253:Astrocytes / Q000473:pathology*; D015153:Blotting, Western; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014746:Vimentin
D005904:Glial Fibrillary Acidic Protein; D015395:Histocompatibility Antigens Class I; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014746:Vimentin