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Chaperoned amyloid proteins for immune manipulation: ?-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.

ABSTRACT: ?-Synuclein (?Syn) is a 140-residue amyloid-forming protein whose aggregation is linked to Parkinson's disease (PD). It has also been found to play a critical role in the immune imbalance that accompanies disease progression, a characteristic that has prompted the search for an effective ?Syn-based immunotherapy. In this study, we have simultaneously exploited two important features of certain heat-shock proteins (HSPs): their classical "chaperone" activities and their recently discovered and diverse "immunoactive" properties. In particular, we have explored the immune response elicited by immunization of C57BL/6 mice with an ?Syn/Hsp70 protein combination in the absence of added adjuvant. Our results show differential effects for mice immunized with the ?Syn/Hsp70 complex, including a restrained ?Syn-specific (IgM and IgG) humoral response as well as minimized alterations in the Treg (CD4(+)CD25(+)Foxp3(+)) and Teff (CD4(+)Foxp3(-)) cell populations, as opposed to significant changes in mice immunized with ?Syn and Hsp70 alone. Furthermore, in vitro-stimulated splenocytes from immunized mice showed the lowest relative response against ?Syn challenge for the "?Syn/Hsp70" experimental group as measured by IFN-? and IL-17 secretion, and higher IL-10 levels when stimulated with LPS. Finally, serum levels of Th1-cytokine IFN-? and immunomodulatory IL-10 indicated a unique shift toward an immunomodulatory/immunoprotective phenotype in mice immunized with the ?Syn/Hsp70 complex. Overall, we propose the use of functional "HSP-chaperoned amyloid/aggregating proteins" generated with appropriate HSP-substrate protein combinations, such as the ?Syn/Hsp70 complex, as a novel strategy for immune-based intervention against synucleinopathies and other amyloid or "misfolding" neurodegenerative disorders.

SUBMITTER: Labrador-Garrido A

PROVIDER: S-EPMC4386917 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Chaperoned amyloid proteins for immune manipulation: α-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.

Labrador-Garrido Adahir A Cejudo-Guillén Marta M Klippstein Rebecca R De Genst Erwin J EJ Tomas-Gallardo Laura L Leal María M MM Villadiego Javier J Toledo-Aral Juan J JJ Dobson Christopher M CM Pozo David D Roodveldt Cintia C

Immunity, inflammation and disease 20141205 4

α-Synuclein (αSyn) is a 140-residue amyloid-forming protein whose aggregation is linked to Parkinson's disease (PD). It has also been found to play a critical role in the immune imbalance that accompanies disease progression, a characteristic that has prompted the search for an effective αSyn-based immunotherapy. In this study, we have simultaneously exploited two important features of certain heat-shock proteins (HSPs): their classical "chaperone" activities and their recently discovered and di ...[more]

PMID: 25866630

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Project description:BackgroundGlioblastoma multiforme (GBM) induces tumor immunosuppression through interacting with tumor-infiltrating microglia or macrophages (TAMs) with an unclear pathogenesis. Enhancer of zeste homolog 2 (EZH2) is abundant in GBM samples and cell lines and is involved in GBM proliferation, cell cycle, and invasion, whereas its association with innate immune response is not yet reported. Herein, the aim of this study was to investigate the role of EZH2 in GBM immune.MethodsCo-culturing models of human/murine GBM cells with PBMC-derived macrophages/primary microglia were employed. EZH2 mRNAs and function were suppressed by siEZH2 and DZNep. Real-time PCR and flow cytometry were used to determine levels of microglia/macrophages markers. The fluorescence-labeled latex beads and flow cytometry were utilized to evaluate phagocytic abilities of microglia. CCK8 assay was performed to assess microglia proliferation.ResultsEZH2 inhibition led to significant reduction of TGF?1-3 and IL10 and elevation of IL1? and IL6 in human and murine GBM cells. More importantly, EZH2 suppression in GBM cells resulted in significant increase of M1 markers (TNF? and iNOS) and decrease of a pool of M2 markers in murine microglia. The proportion of CD206+ cells was decreased in PBMC-derived macrophages as co-incubated with EZH2-inhibited GBM cells. Functional researches showed that phagocytic capacities of microglia were significantly ameliorated after EZH2 inhibition in co-culturing GBM cells and microglia proliferation was declined after addition of TGF?2 antibodies to co-incubated GBM cells with EZH2 inhibition. Besides, we found that EZH2 suppression in GBM cells enhanced co-culturing microglia engulfment through activation of iNOS.ConclusionsOur data demonstrates that EZH2 participates in GBM-induced immune deficient and EZH2 suppression in GBM can remodel microglia immune functions, which is beneficial for understanding GBM pathogenesis and suggests potential targets for therapeutic approaches.

Dataset Information

Chaperoned amyloid proteins for immune manipulation: ?-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.

Publications

Chaperoned amyloid proteins for immune manipulation: α-Synuclein/Hsp70 shifts immunity toward a modulatory phenotype.

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