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Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.

ABSTRACT: Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage, and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated Ag-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2, and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease.

SUBMITTER: Lee EJ

PROVIDER: S-EPMC4799727 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.

Lee Ellen J EJ Brown Brieanna R BR Vance Emily E EE Snow Paige E PE Silver Phyllis B PB Heinrichs David D Lin Xin X Iwakura Yoichiro Y Wells Christine A CA Caspi Rachel R RR Rosenzweig Holly L HL

Journal of immunology (Baltimore, Md. : 1950) 20160226 7

Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA. EAU manife ...[more]

PMID: 26921309

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Project description:BackgroundIntracerebral hemorrhage (ICH) is a severe brain-injured disease accompanied by cerebral edema, inflammation, and subsequent neurological deficits. Mesenchymal stem cells (MSCs) transplantation has been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. Nevertheless, the biological characteristics of transplanted MSCs, including the survival rate, viability, and effectiveness, are restricted because of the severe inflammatory response after ICH. Therefore, improving the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the biomedical applications of coordination chemistry-mediated metal-quercetin complex have been verified positively and studied extensively, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) possesses extraordinary dual capabilities with a stimulating agent for cell growth and an imaging probe by magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH while also labeling MSCs for their tracking by MRI. This study aimed to explore the effects of MSCs with IronQ in regulating inflammation and further clarify their potential mechanisms.MethodsC57BL/6 male mice were utilized in this research. A collagenase I-induced ICH mice model was established and randomly separated into the model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ) after 24 h. Then, the neurological deficits score, brain water content (BWC), and protein expression, such as TNF-α, IL-6, NeuN, MBP, as well as GFAP, were investigated. We further measured the protein expression of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells were utilized to investigate the neuroprotection of conditioned medium of MSCs co-cultured with IronQ in vitro.ResultsWe found that the combined treatment of MSCs with IronQ improved the inflammation-induced neurological deficits and BWC in vivo by inhibiting the Mincle/syk signaling pathway. Conditioned medium derived from MSCs co-cultured with IronQ decreased inflammation, Mincle, and its downstream targets in the LPS-induced BV2 cell line.ConclusionsThese data suggested that the combined treatment exerts a collaborative effect in alleviating ICH-induced inflammatory response through the downregulation of the Mincle/syk signaling pathway following ICH, further improving the neurologic deficits and brain edema.

Dataset Information

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.

Publications

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.

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