Dataset Information

Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1.

ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating autoimmune disease, such as multiple sclerosis (MS), which is characterized by central nervous system white matter lesions, microglial activation, and peripheral T-cell infiltration secondary to blood-brain barrier disruption. We have previously shown that treatment with tuftsin, a tetrapeptide generated from IgG proteolysis, dramatically improves disease symptoms in EAE. Here, we report that microglial expression of Neuropilin-1 (Nrp1) is required for tuftsin-driven amelioration of EAE symptoms. Nrp1 ablation in microglia blocks microglial signaling and polarization to the anti-inflammatory M2 phenotype, and ablation in either the microglia or immunosuppressive regulatory T cells (Tregs) reduces extended functional contacts between them and Treg activation, implicating a role for microglia in the activation process, and more generally, how immune surveillance is conducted in the CNS. Taken together, our findings delineate the mechanistic action of tuftsin as a candidate therapeutic against immune-mediated demyelinating lesions.

SUBMITTER: Nissen JC

PROVIDER: S-EPMC4833601 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1.

Nissen Jillian C JC Tsirka Stella E SE

Glia 20160216 6

Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating autoimmune disease, such as multiple sclerosis (MS), which is characterized by central nervous system white matter lesions, microglial activation, and peripheral T-cell infiltration secondary to blood-brain barrier disruption. We have previously shown that treatment with tuftsin, a tetrapeptide generated from IgG proteolysis, dramatically improves disease symptoms in EAE. Here, we report that microglial expressio ...[more]

PMID: 26880314

Similar Datasets

Project description:BackgroundIntravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism.MethodsWe measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11R?-/-). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11R?-/- mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells.ResultsIVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11R?-/- mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11R?-/- mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11R?-/- mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture.ConclusionThese results implicate IL-11 as an important immune effector of IVIg in the prevention of Th17-mediated autoimmune inflammation during EAE.

Dataset Information

Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1.

Publications

Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets