Leukemia inhibitory factor deficiency modulates the immune response and limits autoimmune demyelination: a new role for neurotrophic cytokines in neuroinflammation.
The neurotrophic cytokines ciliary neurotrophic factor and leukemia inhibitory factor (LIF) play a key role in neuronal and oligodendrocyte survival and as protective factors in neuroinflammation. To further elucidate the potential of endogenous LIF in modulating neuroinflammation, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LIF knockout mice (LIF(-/-) mice). In the late phase of active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, LIF(-/-) mice exhibited a markedly milder disease course. The inflammatory infiltrate in LIF(-/-) mice was characterized by an increase in neutrophilic granulocytes early and fewer infiltrating macrophages associated with less demyelination later in the disease. In good correlation with an effect of endogenous LIF on the immune response, we found an Ag-specific T cell-priming defect with impaired IFN-gamma production in LIF(-/-) mice. On the molecular level, the altered recruitment of inflammatory cells is associated with distinct patterns of chemokine production in LIF(-/-) mice with an increase of CXCL1 early and a decrease of CCL2, CCL3, and CXCL10 later in the disease. These data reveal that endogenous LIF is an immunologically active molecule in neuroinflammation. This establishes a link between LIF and the immune system which was not observed in the ciliary neurotrophic factor knockout mouse.
Linker
Ralf A
RA
Institute for Multiple Sclerosis Research, University of Goettingen and Gemeinnuetzige Hertie-Stiftung, Goettingen, Germany. ralf.linker@rub.de
Kruse
Niels
N
Israel
Stephanie
S
Wei
Tao
T
Seubert
Silvia
S
Hombach
Anja
A
Holtmann
Bettina
B
Luhder
Fred
F
Ransohoff
Richard M
RM
Sendtner
Michael
M
Gold
Ralf
R
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018925:Chemokines / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000276:immunology / Q000633:toxicity; D053605:Leukemia Inhibitory Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D053606:Receptors, OSM-LIF / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D018925:Chemokines; D006023:Glycoproteins; D053605:Leukemia Inhibitory Factor; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D053606:Receptors, OSM-LIF; C445081:myelin oligodendrocyte glycoprotein (35-55)