sirt1-null mice develop an autoimmune-like condition

Sequeira, Jedon; Boily, Gino; Bazinet, Stephanie; Saliba, Sarah; He, Xiaohong; Jardine, Karen; Kennedy, Christopher J.; Staines, W.A.; Rousseaux, Colin G.; Mueller, Robert F.; McBurney, Michael W.

doi:10.1016/j.yexcr.2008.07.011

Cited by 127 publications

(120 citation statements)

References 21 publications

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“…The contribution of depressed Sirt1 activity to pathology in COPD is suggested by the observation that genetic silencing of Sirt1 expression in human monocytic cell lines enhances NF-kB transcriptional activity and homeostatic IL-8 production (20). Additionally, mice genetically deficient for Sirt1 develop autoimmune disease marked by Ab deposition in liver and kidneys and symptoms of diabetes (51). Together, these observations would predict that pharmacological inhibition of sirtuin promotes inflammation.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Suppress Inflammatory Activation of Rheumatoid Arthritis Patient Synovial Macrophages and Tissue

Grabiec

Krausz

Jager

et al. 2010

The Journal of Immunology

201

142

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Macrophages contribute significantly to the pathology of many chronic inflammatory diseases, including rheumatoid arthritis (RA), asthma, and chronic obstructive pulmonary disease. Macrophage activation and survival are tightly regulated by reversible acetylation and deacetylation of histones, transcription factors, and structural proteins. Although histone deacetylase (HDAC) inhibitors (HDACis) demonstrate therapeutic effects in animal models of chronic inflammatory disease, depressed macrophage HDAC activity in patients with asthma, chronic obstructive pulmonary disease, or RA may contribute to inflammation in these diseases, potentially contraindicating the therapeutic administration of HDACis. In this study, we directly examined whether HDACis could influence the activation of macrophages derived from the inflamed joints of patients with RA. We found that inhibition of class I/II HDACs or class III sirtuin HDACs potently blocked the production of IL-6 and TNF-α by macrophages from healthy donors and patients with RA. Two HDACis, trichostatin A and nicotinamide, selectively induced macrophage apoptosis associated with specific downregulation of the antiapoptotic protein Bfl-1/A1, and inflammatory stimuli enhanced the sensitivity of macrophages to HDACi-induced apoptosis. Importantly, inflammatory and angiogenic cytokine production in intact RA synovial biopsy explants was also suppressed by HDACis. Our study identifies redundant, but essential, roles for class I/II and sirtuin HDACs in promoting inflammation, angiogenesis, and cell survival in RA.

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Suppress Inflammatory Activation of Rheumatoid Arthritis Patient Synovial Macrophages and Tissue

Grabiec

Krausz

Jager

et al. 2010

The Journal of Immunology

201

142

View full text Add to dashboard Cite

show abstract

“…Given the fact that blockade of NF-B in the skin of aged mice can induce the reversal of many features of aging (88), the key role of NF-B in inflammation as a chemical modulator of sirtuin activity could emerge in novel drugs of therapeutic relevance to age-related inflammatory disorders. Of interest, young sirt1-null animals develop an autoimmune-like condition that resembles SLE and those that survive up to 2 years of age have a disease resembling diabetes insipidus (89). More studies will definitely be needed to understand the functional significance of all these observations in the general immune dysfunction of the elderly and their higher predisposition to immune-mediated diseases.…”

Section: Epigenetics: a Novel Therapeutic Intervention?mentioning

confidence: 99%

Epigenetics, aging, and autoimmunity

Yung

Julius

2008

Autoimmunity

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The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.

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“…As a consequence, SIRT1 -/-mice display an increased T cell responsiveness in vitro and Page 10 of 28 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 are predisposed to develop autoimmune disorders, a conclusion further confirmed by an independent study [40].…”

Section: Sirt1 Inhibits Ap-1 By Deacetylating C-jun and C-fosmentioning

confidence: 64%

Sirtuins and inflammation: Friends or foes?

Gallí

Gool

Léo

2011

Biochemical Pharmacology

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Lysine acetylation/deacetylation has been recognized as an important posttranslational modification regulating numerous cellular processes. Sirtuins represent novel players in these complex regulatory circuits. These NAD-dependent lysine-deacetylases have attracted much interest based on their role in the regulation of lifespan in lower organisms, and their capacity to interfere with cell growth, proliferation and survival in response to stress. Their absolute requirement for NAD suggests that these enzymes may represent an important molecular link between metabolism and several human disorders such as diabetes and cancer. More recently, the identification of several transcription factors known to play a role in the immune system as sirtuin substrates has suggested that this family of enzymes may also play an important role in the regulation of inflammation, a pathological situation with clear links to metabolism and ageing in humans. We review herein the possible links between nuclear sirtuins and the regulation of an immune response, and discuss the possible strategies that may lead to the development of novel therapeutic approaches to treat inflammation by targeting sirtuin activity.

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sirt1-null mice develop an autoimmune-like condition

Cited by 127 publications

References 21 publications

Histone Deacetylase Inhibitors Suppress Inflammatory Activation of Rheumatoid Arthritis Patient Synovial Macrophages and Tissue

Histone Deacetylase Inhibitors Suppress Inflammatory Activation of Rheumatoid Arthritis Patient Synovial Macrophages and Tissue

Epigenetics, aging, and autoimmunity

Sirtuins and inflammation: Friends or foes?

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