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New Pathways With Promise in AD—An Inflammatory Statement?
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26 September 2009. This week, a pair of papers shine a spotlight on the pathways—one in astrocytes, one in microglia—that regulate inflammation in Alzheimer disease. The first, from Ilo Jou and colleagues at Ajou University School of Medicine, Suwon, Korea, delves into the anti-inflammatory actions of liver X receptors (LXRs). Better known to AD researchers for their effects on cholesterol and Aβ transport, LXRs also block cytokine gene expression in stimulated brain astrocytes, and the researchers show that they directly inhibit binding of the transcription factor STAT1 to inflammatory gene promoters. Published in today’s issue of Molecular Cell, the work suggests new ways to target the LXRs to deliver a double whammy in AD, by both reducing Aβ and quieting neuroinflammation. The second paper, from Gary Landreth and colleagues of Case Western Reserve University in Cleveland, Ohio, shows how fibrillar Aβ instigates inflammatory microglia activation through the receptors of the innate immune system.
The LXRs are sterol-binding nuclear proteins that are already considered promising targets for new approaches to treat AD, based on their effects on Aβ. Their activation by synthetic ligands increases expression of ApoE and the ABCA1 transporter, both of which enhance Aβ clearance. More than that, the LXRs and related nuclear receptors also inhibit inflammatory gene expression. In AD mouse models, loss of LXRs exacerbates plaque pathology, possibly through effects on inflammation (see ARF related news story on Zelcer et al., 2007), Aβ clearance (see ARF related news story on Jiang et al., 2008), or both.
To understand the anti-inflammatory action of LXR ligands, first author Jee Hoon Lee and colleagues looked at the effects of LXR agonists on IFNγ-induced inflammatory gene expression, which is mediated by activation of the STAT1 transcription factor in cultured rat astrocytes. LXR ligands did not inhibit the activation or nuclear translocation of STAT1, the researchers found, but instead blocked binding of the factor to DNA. The effect was direct—by coimmunoprecipitation, the researchers showed that the two isoforms LXRα and LXRβ each participate in a unique tri-protein complex with STAT1 and a different small, ubiquitin-like modifier (SUMO) E3 ligase (PIAS1 or HDAC4, respectively). In the complex, the ligases SUMOylated the LXRs, and this modification was required for STAT inhibition. The pathway resembles how LXRs inhibit another pro-inflammatory transcription factor, NFκB, via the same modification (Ghisletti et al., 2007).
Landreth told ARF, “This is a really elegant demonstration of how modification, in this case by SUMOylation, of the LXRs has rather specific effects on a unique signaling pathway.” Landreth, who was not involved in the work, continued, “Most people have focused on the fact that LXRs are cholesterol sensors. Their capacity to shut down inflammation is a really important feature, and the cool thing is that it works through completely different mechanisms.”
In a preview accompanying the paper, Bin Liu and Ke Shuai at the University of California at Los Angeles highlight the emerging role of nuclear receptors including the LXRs and peroxisome proliferator-activator receptors (PPARs) as a major class of anti-inflammatory regulators, with a potential to yield novel targets for drug development.
The Landreth group has their own paper out this week in the September 23 Journal of Neuroscience, looking at how fibrillar Aβ ignites inflammation in microglia, the brain’s resident macrophages. Lead author Erin G. Reed-Geaghan used knockout mice lacking the LPS receptor CD14 or either of the Toll-like receptors TLR2 and TLR4 to show that the presence of all three is necessary for binding of amyloid fibrils and activation of microglia. Aβ treatment of cells lacking any of the three receptors did not trigger the Src or p38 map kinase signaling cascades, nor did it activate NFκB, produce reactive oxygen species, or stimulate phagocytosis.
Previous work from other labs (Fassbender et al., 2004) has implicated CD14 in the response to fibrillar Aβ, and the current work extends those findings by linking CD14 to Aβ-induced signaling cascades. “Our paper solves mechanistic riddles about how microglia undergo this classical pro-inflammatory activation, by showing they use the standard well-developed host defense machinery these cells were evolved to employ,” Landreth told ARF.
As if three receptors weren’t enough, others are involved, too. Landreth had previously reported that the α6β1 integrin, CD36, CD47, and class A scavenger receptor are also part of a large, multi-component receptor system for fibrillar Aβ (Bamberger et al., 2003). That fits with the idea that the innate immune response is engaged by fibrillar Aβ, Landreth says. “The situation is analogous to how bacteria and other complex molecules use a whole panoply of receptors on macrophages. The innate immune system uses non-specific receptors in combination to detect complex antigens.”—Pat McCaffrey.
References:
Lee JH, Park SM, Kim OS, Lee CS, Woo JH, Park SJ, Joe E, Jou I. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-g-stimulated Brain Astrocytes. Molecular Cell. 2009 September 25; 35:805-817. Abstract
Liu B, Shuai K. Summon SUMO to wrestle with inflammation. Molecular Cell. 2009 September 25; 35:731-732. Abstract
Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Ab-stimulated microglia activation. J. Neurosci. 2009 September 23; 29(38):11982-11992. Abstract
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Primary Papers: Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.
Comment by: Radosveta Koldamova, Iliya Lefterov
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Submitted 30 September 2009
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Posted 30 September 2009
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In this article, Lee et al. examine the mechanism by which Liver X Receptors (LXRα /b) inhibit inflammation in astrocytes. LXR are key transcriptional regulators of cholesterol and lipid metabolism, and LXR agonists were shown to decrease amyloid deposition in APP transgenic mice (1-3). LXR ligands, and thus activated LXR, inhibit inflammation in the periphery as well as in the brain, but how they do that was a mystery (4,5).
In this study, the authors use primary astrocytes from rat brain that were stimulated by IFN-g to produce inflammatory cytokines. Lee et al. concentrate on signal transduction activity and enhancement of transcription (STAT1) signaling pathways. First, they prove that LXR ligands do not affect the phosphorylation or nuclear translocation of STAT1, but rather prevent its binding to the promoter. Next, using a series of elegant and convincing experiments, Lee et al. prove that the suppressive actions of LXR ligands on STAT1 inflammatory signaling are LXR-receptor dependent. It means that LXRα and LXRβ use slightly different but still similar ways to...
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In this article, Lee et al. examine the mechanism by which Liver X Receptors (LXRα /b) inhibit inflammation in astrocytes. LXR are key transcriptional regulators of cholesterol and lipid metabolism, and LXR agonists were shown to decrease amyloid deposition in APP transgenic mice (1-3). LXR ligands, and thus activated LXR, inhibit inflammation in the periphery as well as in the brain, but how they do that was a mystery (4,5).
In this study, the authors use primary astrocytes from rat brain that were stimulated by IFN-g to produce inflammatory cytokines. Lee et al. concentrate on signal transduction activity and enhancement of transcription (STAT1) signaling pathways. First, they prove that LXR ligands do not affect the phosphorylation or nuclear translocation of STAT1, but rather prevent its binding to the promoter. Next, using a series of elegant and convincing experiments, Lee et al. prove that the suppressive actions of LXR ligands on STAT1 inflammatory signaling are LXR-receptor dependent. It means that LXRα and LXRβ use slightly different but still similar ways to inhibit STAT1, which is very unexpected. The similarity is in the inhibition of STAT1 caused by SUMOylation of LXRα and LXRβ . The authors found a difference as well—the SUMOylation was mediated through different SUMO E ligases. LXRα was SUMOylated by HDAC4, which is both a SUMO E3 ligase and a histone deacetylase, and LXRβ by PIAS1, which is another SUMO 3 ligase. This is a very interesting finding and, as the authors state, the specific regulation of LXRα and LXRβ through SUMOylation can be exploited therapeutically in Alzheimer disease and stroke.
References:
1. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the proteolytic degradation of Abeta. Neuron 2008;58:681-93. Abstract
2. Koldamova R, Lefterov I. Role of LXR and ABCA1 in the Pathogenesis of Alzheimer's Disease - Implications for a New Therapeutic Approach. Curr.Alzheimer Res. 2007;4:171-8. Abstract
3. Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS. The Liver X Receptor Ligand T0901317 Decreases Amyloid {beta} Production in Vitro and in a Mouse Model of Alzheimer's Disease. J.Biol.Chem. 2005;280:4079-88. Abstract
4. Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol.Neurodegener. 2007;2:20. Abstract
5. Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc.Natl.Acad.Sci.U.S.A 2007;104:10601-6. Abstract
 View all comments by Radosveta Koldamova
View all comments by Iliya Lefterov |
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Primary Papers: Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.
Comment by: Veronique Dorval
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Submitted 3 October 2009
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Posted 3 October 2009
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The present study assesses the control of inflammatory signaling by SUMOylation of nuclear receptors in immunity. LXRα/β are ligand-activated nuclear receptors that can inhibit the expression of inflammatory genes. It is known that inflammation contributes to several human pathologies, including Alzheimer disease (AD). SUMOylation is a post-translational modification, and the interest for the identification of substrates and functions keep growing. It has been shown that tau, involved in AD neurofibrillary tangles, is a SUMO substrate. And a fast-growing number of SUMO substrates are identified in healthy and disease neurons. Here, Lee and colleagues demonstrate a new link between SUMO and inflammation.
Using rat brain astrocytes, the authors showed that the expression of STAT1-regulated inflammatory genes is negatively regulated by the formation of the trimeric complexes HDAC4/STAT1/LXRα and PIAS1/STAT1/LXRβ. PIAS1 and HDAC4 are known SUMO ligases, and in addition to their presence in the complexes, the authors showed that LXRs are SUMOylated in the trimers. These complexes...
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The present study assesses the control of inflammatory signaling by SUMOylation of nuclear receptors in immunity. LXRα/β are ligand-activated nuclear receptors that can inhibit the expression of inflammatory genes. It is known that inflammation contributes to several human pathologies, including Alzheimer disease (AD). SUMOylation is a post-translational modification, and the interest for the identification of substrates and functions keep growing. It has been shown that tau, involved in AD neurofibrillary tangles, is a SUMO substrate. And a fast-growing number of SUMO substrates are identified in healthy and disease neurons. Here, Lee and colleagues demonstrate a new link between SUMO and inflammation.
Using rat brain astrocytes, the authors showed that the expression of STAT1-regulated inflammatory genes is negatively regulated by the formation of the trimeric complexes HDAC4/STAT1/LXRα and PIAS1/STAT1/LXRβ. PIAS1 and HDAC4 are known SUMO ligases, and in addition to their presence in the complexes, the authors showed that LXRs are SUMOylated in the trimers. These complexes cannot bind to genes promoters, inhibiting the expression of inflammatory genes. A role for SUMO in this nuclear processing is not surprising. It is one of the major, not exclusive, role of SUMOylation.
The specificity between SUMOylation of LXRα by SUMO2 and LXRβ by SUMO1 is puzzling and not addressed in the present paper. SUMO2 and SUMO3 share 95 percent sequence homology, and the specificity of SUMO2, as compared to SUMO3, has not been taken into consideration. Interesting future studies will likely include the crosstalk between both LXRs, the effect of different stimulating ligands, and the crosstalk with other inflammatory signaling pathways.
Overall, this is an interesting paper and adds to a better understanding of the regulation of inflammation. It can lead to the development of new therapeutic avenues that would benefit uncontrolled inflammatory pathogeneses, including Alzheimer disease. Of course, this is not in the near future, but the research should be exploited.
View all comments by Veronique Dorval |
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