Myelin-specific T cells induce interleukin-1beta expression in lesion-reactive microglial-like cells in zones of axonal degeneration.
Infiltration of myelin-specific T cells into the central nervous system induces the expression of proinflammatory cytokines in patients with multiple sclerosis (MS). We have previously shown that myelin-specific T cells are recruited into zones of axonal degeneration, where they stimulate lesion-reactive microglia. To gain mechanistic insight, we used RNA microarray analysis to compare the transcript profile in hippocampi from perforant pathway axonal-lesioned mice with and without adoptively transferred myelin-specific T cells 2 days postlesion, when microglia are clearly lesion reactive. Pathway analysis revealed that, among the 1,447 differently expressed transcripts, the interleukin (IL)-1 pathway including all IL-1 receptor ligands was upregulated in the presence of myelin-specific T cells. Quantitative polymerase chain reaction showed increased mRNA levels of IL-1β, IL-1α, and IL-1 receptor antagonist in the T-cell-infiltrated hippocampi from axonal-lesioned mice. In situ hybridization and immunohistochemistry showed a T-cell-enhanced lesion-specific expression of IL-1β mRNA and protein, respectively, and induction of the apoptosis-associated speck-like protein, ASC, in CD11b(+) cells. Double in situ hybridization showed colocalization of IL-1β mRNA in a subset of CD11b mRNA(+) cells, of which many were part of cellular doublets or clusters, characteristic of proliferating, lesion-reactive microglia. Double-immunofluorescence showed a T-cell-enhanced colocalization of IL-1β to CD11b(+) cells, including lesion-reactive CD11b(+) ramified microglia. These results suggest that myelin-specific T cells stimulate lesion-reactive microglial-like cells to produce IL-1β. These findings are relevant to understand the consequences of T-cell infiltration in white and gray matter lesions in patients with MS.
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Manuela
M
Grebing
Department of Neurology, Odense University Hospital, Odense C, Denmark.
Helle H
HH
Nielsen
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Christina D
CD
Fenger
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Katrine
K
T Jensen
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Christian U
CU
von Linstow
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Bettina H
BH
Clausen
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Martin
M
Söderman
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Kate L
KL
Lambertsen
Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
Mads
M
Thomassen
Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
Torben A
TA
Kruse
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.
Bente
B
Finsen
D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D017628:Microglia / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000473:pathology*; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
D016207:Cytokines; D005452:Fluoresceins; D053583:Interleukin-1beta; D012333:RNA, Messenger; C435731:fluoro jade
Wallerian degeneration; cytokines; demyelination; gray matter; multiple sclerosis