Abstract
BackgroundThe inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC−/− mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS.MethodsWe employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55). Mice were treated with vehicle or increasing doses of IC100 (10, 30, and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.ResultsWe show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia.ConclusionsThese data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.
Highlights
The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1
Our data reveal that administration of IC100 (30 mg/kg) in Myelin oligodendrocyte glycoprotein (MOG)-induced EAE resulted in significant decrease in the number of CD4+, CD8+, and CD11b+MHCII+ cells in the spinal cord resulting in protection from EAE
This dose of IC100 decreased the numbers of total and activated microglia in the spinal cord and resulted in improved clinical scores. These findings are consistent with our previous studies demonstrating that antibody-mediated neutralization of a caspase recruitment domain (ASC) results in significant functional improvements in the spinal cord [10] and brain trauma [48] injury models
Summary
The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC−/− mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. The goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by an inflammatory response sustained by innate and adaptive immune mechanisms dependent on lymphocyte (both T and B cells) and myeloid cell activation [1]. The understanding of MS pathomechanisms as well as the development of MS therapeutics has relied upon the use of the experimental autoimmune encephalomyelitis (EAE) model. Many of the disease-modifying drugs currently in clinical use have been developed after successful testing in EAE [4]
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