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Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

ABSTRACT: Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope ?377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

SUBMITTER: Ryu JK

PROVIDER: S-EPMC6317891 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Ryu Jae Kyu JK Rafalski Victoria A VA Meyer-Franke Anke A Adams Ryan A RA Poda Suresh B SB Rios Coronado Pamela E PE Pedersen Lars Østergaard LØ Menon Veena V Baeten Kim M KM Sikorski Shoana L SL Bedard Catherine C Hanspers Kristina K Bardehle Sophia S Mendiola Andrew S AS Davalos Dimitrios D Machado Michael R MR Chan Justin P JP Plastira Ioanna I Petersen Mark A MA Pfaff Samuel J SJ Ang Kenny K KK Hallenbeck Kenneth K KK Syme Catriona C Hakozaki Hiroyuki H Ellisman Mark H MH Swanson Raymond A RA Zamvil Scott S SS Arkin Michelle R MR Zorn Stevin H SH Pico Alexander R AR Mucke Lennart L Freedman Stephen B SB Stavenhagen Jeffrey B JB Nelson Robert B RB Akassoglou Katerina K

Nature immunology 20181015 11

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody ...[more]

PMID: 30323343

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Project description:BackgroundSynucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2).MethodsTwo different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission.ResultsWe demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses.ConclusionThis study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.

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Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Publications

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

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