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Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine.

ABSTRACT: Although certain dogma portrays amyloid fibrils as drivers of neurodegenerative disease and neuroinflammation, we have found, paradoxically, that amyloid fibrils and small heat shock proteins (sHsps) are therapeutic in experimental autoimmune encephalomyelitis (EAE). They reduce clinical paralysis and induce immunosuppressive pathways, diminishing inflammation. A key question was the identification of the target for these molecules. When sHsps and amyloid fibrils were chemically cross-linked to immune cells, a limited number of proteins were precipitated, including the ?7 nicotinic acetylcholine receptor (?7 NAChR). The ?7 NAChR is noteworthy among the over 20 known receptors for amyloid fibrils, because it plays a central role in a well-defined immune-suppressive pathway. Competitive binding between amyloid fibrils and ?-bungarotoxin to peritoneal macrophages (M?s) confirmed the involvement of ?7 NAChR. The mechanism of immune suppression was explored, and, similar to nicotine, amyloid fibrils inhibited LPS induction of a common set of inflammatory cytokines while inducing Stat3 signaling and autophagy. Consistent with this, previous studies have established that nicotine, sHsps, and amyloid fibrils all were effective therapeutics in EAE. Interestingly, B lymphocytes were needed for the therapeutic effect. These results suggest that agonists of ?7 NAChR might have therapeutic benefit for a variety of inflammatory diseases.

SUBMITTER: Rothbard JB

PROVIDER: S-EPMC6142248 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine.

Rothbard Jonathan B JB Rothbard Jesse J JJ Soares Luis L Fathman C Garrison CG Steinman Lawrence L

Proceedings of the National Academy of Sciences of the United States of America 20180618 27

Although certain dogma portrays amyloid fibrils as drivers of neurodegenerative disease and neuroinflammation, we have found, paradoxically, that amyloid fibrils and small heat shock proteins (sHsps) are therapeutic in experimental autoimmune encephalomyelitis (EAE). They reduce clinical paralysis and induce immunosuppressive pathways, diminishing inflammation. A key question was the identification of the target for these molecules. When sHsps and amyloid fibrils were chemically cross-linked to ...[more]

PMID: 29915045

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Project description:BackgroundThe effects of diverse stresses ultimately alter the structures and functions of proteins. As molecular chaperones, heat shock proteins (HSPs) are a group of highly conserved proteins that help in the refolding of misfolded proteins and the elimination of irreversibly damaged proteins. They are mediated by a family of transcription factors called heat shock factors (HSFs). The small abalone Haliotis diversicolor is a species naturally distributed along the southern coast of China. In this study, the expression of HdHSF1 was inhibited by RNAi in hemocytes in order to further elucidate the regulatory roles of HdHSF1 on heat shock responsive genes in abalone. Meanwhile, to understand the transcriptional regulation of the HdHSF1 gene, the 5'-upstream regulatory region of HdHSF1 was characterized, and the relative promoter activity was examined by dual-luciferase reporter gene assay system in HEK293T cell lines.ResultsAfter the inhibition of the H. diversicolor HSF1 gene (HdHSF1) by dsRNA (double-stranded RNA), the expression of most heat shock related-genes was down-regulated (p < 0.05). It indicated the importance of HdHSF1 in the heat shock response of H. diversicolor. Meanwhile, 5'-flanking region sequence (2633 bp) of the HdHSF1 gene was cloned; it contained a putative core promoter region, TATA box, CAAT box, CpG island, and many transcription elements. In HEK293T cells, the 5'-flanking region sequence can drive expression of the enhanced green fluorescent protein (EGFP), proving its promoter function. Exposure of cells to the high-temperature (39 °C and 42 °C) resulted in the activation of HdHSF1 promoter activity, which may explain why the expression of the HdHSF1 gene participates in heat shock response. Luciferase activity of different recombinant plasmids, which contained different truncated promoter fragments of the HdHSF1 gene in HEK293T cells, revealed the possible active regions of the promoter. To further identify the binding site of the critical transcription factor in the region, an expression vector with the site-directed mutation was constructed. After being mutated on the GATA-1 binding site, we found that the luciferase activity was significantly increased, which suggested that the GATA-1 binding site has a certain weakening effect on the activity of the HdHSF1 promoter.ConclusionsThese findings suggest that GATA-1 may be one of the transcription factors of HdHSF1, and a possible signaling pathway mediated by HdHSF1 may exist in H. diversicolor to counteract the adverse effects of heat shock stress.

Dataset Information

Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine.

Publications

Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine.

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