Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Shimp, Samuel K.; Chafin, Cristen B.; Regna, Nicole L.; Hammond, Sarah; Read, Molly A; Caudell, David L.; Rylander, Marissa Nichole; Reilly, Christopher M.

doi:10.1038/cmi.2012.5

Cited by 53 publications

(52 citation statements)

References 96 publications

(123 reference statements)

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“…In fact, DMAG-treated mice exhibited reduced macrophage and T-cell infiltration along with a decreased expression of proinflammatory genes (TNF-a, CCL2, and CCL5). Previous reports indicated that HSP90 inhibitors prevent inflammatory gene expression in different cell types, including cancer cells (36), leukocytes (17,37), and renal and vascular cells (15,17). In line with this, our studies in cultured mesangial and tubular cells mimicking hyperglycemic and inflammatory diabetic conditions demonstrated that DMAG inhibited the gene expression and protein secretion of CCL2 and also mitigated macrophage chemotaxis, further substantiating the in vivo findings.…”

Section: Discussionsupporting

confidence: 78%

“…Preclinical data implicate HSP90 as a promising anti-inflammatory target in rheumatoid arthritis, systemic lupus erythematosus, uveitis, liver injury, and cardiovascular disease models (12,(15)(16)(17)(18). In diabetic animals, HSP90 inhibition improved insulin sensitivity (19), high-fat diet-induced renal failure (20), and neurodegeneration (21), but the underlying mechanisms involved in these antidiabetic actions are not well defined.…”

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confidence: 99%

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Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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Section: Discussionsupporting

confidence: 78%

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confidence: 99%

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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“…They bind to the ATP-binding domain of Hsp90 and disrupt its association with client proteins [20,21]. Recently, Shimp et al have shown that administration of 17-DMAG ameliorated SLE symptoms [22]. However, underlying mechanism has been unclear.…”

Section: Introductionmentioning

confidence: 99%

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease, and disease activity is associated with serum IFN-α level. Plasmacytoid dendritic cells (pDCs) sense microbial as well as self-nucleic acids by TLRs 7 and 9 and produce a large amount of IFN-α. Here, we show that heat shock protein 90 (Hsp90) associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Inhibition of Hsp90 by various approaches including the use of Hsp90 inhibitor, a geldanamycin derivative, suppressed the Hsp90 association with TLR7/9, which resulted in inhibition of IFN-α production, leading to improvement of SLE symptoms in mice. Notably, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Furthermore, we demonstrated that serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Our data demonstrate that Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases.Keywords: Hsp90 r IFN-α r Plasmacytoid DC r SLE r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is characterized by the generation of autoantibodies specific for native double-stranded (ds) Correspondence: Prof. Yasuaki Tamura e-mail: ytamura3566@gmail.com DNA and nucleic acid/protein complexes [1]. A growing body of evidence suggests that IFN-α promotes lupus [2], since many patients have elevated serum IFN-α levels [3,4] and PBMCs from patients exhibit an IFN-α-induced gene expression signature that correlates with disease severity [5,6]. Recent findings in both human and mouse models suggest that TLR7 and TLR9 may play central roles in maintenance and progression of the disease by C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2028-2041 Innate immunity 2029 promoting elevation of IFN-α levels from plasmacytoid dendritic cells (pDCs) [7][8][9] and by activating B cells to produce autoantibodies [10,11]. pDCs sense microbial nucleic acids by TLR7 and TLR9 and produce a large amount of IFN-α. pDCs specifically express TLR7 and TLR9 within endolysosmes, and TLR7 and TLR9 sense single-stranded RNA and unmethylated CpG-rich DNA [12][13][14][15]. Importantly, microbial nucleic acids share a basic structure with host-derived nucleic acids. Indeed, TLR9 is able to respond to mammalian DNA if expressed on the cell surface [16]. TLR7 also responds to host-derived single-stranded RNA [7]. Therefore, nucleic acid-sensing TLR7/9 has to be tightly controlled to avoid autoimmune reaction. Nucleic acid sensing within endolysosomes is thought to be a safety mechanism for self-nucleic acid, because self-nucleic acids are rapidly degraded by DNase and RNase before reaching endolysosomes. Self-derived nuc...

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“…Pharmacological inhibition of Hsp90 function has therefore emerged as a promising method to ameliorate inflammatory cascades, as it has been demonstrated in various experimental mouse models of autoimmune diseases, including autoimmune encephalomyelitis (Dello Russo et al 2006), rheumatoid arthritis (Rice et al 2008;Yun et al 2011), and systemic lupus erythematosus (Han et al 2010;Shimp et al 2012a). Our own recent research work showed that, by downregulating T cell responses, this kind of treatment is also effective in mice with the experimentally induced subepidermal autoimmune blistering skin disease epidermolysis bullosa acquisita (Kasperkiewicz et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

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Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Cited by 53 publications

References 96 publications

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

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