Local Overexpression of Interleukin-11 in the Central Nervous System Limits Demyelination and Enhances Remyelination

Abstract

Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytes in vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1+ mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2+). We further demonstrated that IL-11 directly reduces myelin phagocytosis in vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2+ OPCs into myelinating CC1+ OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination.

Optimal Attenuation of Experimental Autoimmune Encephalomyelitis by Intravenous Immunoglobulin Requires an Intact Interleukin-11 Receptor

“…More recently, it was shown that overexpression of IL-11 in the brain reduces the extent of demyelination and enhances remyelination in the cuprizone-induced demyelinating disease model [57]. We did not observe histologic evidence of more severe demyelination in IL-11Rα −/− mice during EAE.…”

GM2 ganglioside accumulation causes neuroinflammation and behavioral alterations in a mouse model of early-onset Tay-Sachs disease.

“…Moreover, it was reported that deletion of Ccl3 gene caused a delay of neuronal loss in Sandhoff mice (Hexb-/-Mip1α-/-mice) by inhibiting macrophage infiltration to the inflammatory sites, which resulted in improved neurologic status and a longer lifespan (Wu and Proia 2004). Additionally, Hexb-/-Tnfα-/-mice resulted in a delayed neurodegenerative cascade by an extending lifespan, improving sensorimotor coordination, decreasing levels of astrogliosis and neuronal cell death [53]. We suggest that adding antagonists of pro-inflammatory cytokines and chemokines such as Ccl3 or Ccl4 in daily feeding of Hexa-/-Neu3-/mice may reverse neuroinflammatory conditions.…”

Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment

“…We next examined levels of IL‐11, an anti‐inflammatory cytokine with known immunomodulatory and neuroprotective properties (Maheshwari et al, ; Trepicchio and Dorner, ; Trepicchio et al, ; Zhang et al, ). Semiquantitative RT‐PCR measurement of IL‐11 mRNA revealed an increase in IL‐11 expression, as well as an expected reduction in TNFα expression in EE versus NE brains (Fig.…”