IL-11 regulates autoimmune demyelination.
Current therapies for the autoimmune demyelinating disease multiple sclerosis (MS) target inflammation, but do not directly address neuroprotection or lesion repair. Cytokines of the gp130 family regulate survival and differentiation of both neural and immune cells, and we recently identified expression of the family member IL-11 in active MS plaques. In this study, we show that IL-11 regulates the clinical course and neuropathology of experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of MS. Importantly, the effects of IL-11 are achieved via a combination of immunoregulation and direct neuroprotection. IL-11R-alpha-null (IL-11Ralpha(-/-)) mice displayed a significant increase in clinical severity and neuropathology of experimental autoimmune encephalomyelitis compared with wild-type littermates. Inflammation, demyelination, and oligodendrocyte and neuronal loss were all exacerbated in IL-11Ra(-/-) animals. Conversely, wild-type mice treated with IL-11 displayed milder clinical signs and neuropathology than vehicle-treated controls. In cocultures of murine myelin oligodendrocyte glycoprotein(35-55)-specific CD4+ T lymphocytes and CD11c+ APCs, IL-11 treatment resulted in a significant decrease in T cell-derived effector cytokine production. This effect was generated via modulation of CD11c+ APC-mediated lymphocyte activation, and was associated with a decrease in the size of the CD11c+ cell population. Conversely, IL-11 strongly reduced apoptosis and potentiated mitosis in primary cultures of mouse oligodendrocyte progenitors. Collectively, these data reveal that IL-11 regulates inflammatory demyelination via a unique combination of immunoregulation and neuroprotection. IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.
Gurfein
Blake T
BT
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zhang
Yueting
Y
López
Carolina B
CB
Argaw
Azeb Tadesse
AT
Zameer
Andleeb
A
Moran
Thomas M
TM
John
Gareth R
GR
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism* / Q000502:physiology; D039521:CD11c Antigen / Q000096:biosynthesis; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D017370:Interleukin-11 / Q000502:physiology*; D053703:Interleukin-11 Receptor alpha Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000378:metabolism; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques
D001323:Autoantibodies; D039521:CD11c Antigen; C508611:IL11 protein, human; C508429:Il11ra1 protein, mouse; D018836:Inflammation Mediators; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D018696:Neuroprotective Agents