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.
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