ATLANTA—Rheumatologists are well aware that patients with rheumatoid arthritis (RA) and other chronic inflammatory disorders are at an increased risk of developing cardiovascular disease. It has also been established that high-density lipoprotein (HDL) levels correlate inversely with cardiovascular risk. Recent research, such as the study by Carpintero et al, which was led by a team of Swiss, Italian, and Australian investigators, have begun to narrow in on HDL’s ability to interfere with T-cell binding to monocytes, inhibiting production of proinflammatory cytokines.1
These discoveries have led to an important question: Might the intersection of cholesterol metabolism, atherogenesis, and inflammatory signaling offer a potential pathway for interventional strategies to combat inflammatory disease? These were the questions addressed by the research scientists who presented at the session, “A Critical Role for Lipid Metabolism in the Interplay between Atherosclerosis and Autoimmune Disorders.” [Editor’s Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.]
Kerry-Anne Rye, PhD, a professor at the University of Sydney, Australia, addressed the question: “Is it possible to use HDL to attenuate arthritis?” She and her group have conducted experiments at the Heart Research Institute of Sydney, where she is associate director, aimed at exploring a possible use of HDL to counteract the inflammatory processes that result in joint erosion.
Dr. Rye prefaced her presentation of her group’s current work with a succinct description of HDLs. Although we commonly use one term to refer to high-density lipoproteins, she noted, they do not comprise a single entity. Rather, HDLs are a complex series of subpopulations of particles, all of which are continually being interconverted from one to another by a range of factors in the circulation. HDLs, she said, “start off as discoidal particles consisting of a phospholipid bilayer surrounded by apolipoproteins,” and are classified according to the presence of one or both of their main constituent apolipoproteins, apoA-1 and apoA-2.
Able to Alleviate Inflammation?
One of the antiatherogenic functions of HDL is its ability to efflux cholesterol, especially from macrophages in the artery walls. HDL also has antithrombotic, antiinflammatory, and antioxidant properties. There may be other beneficial properties of HDL which have yet to be identified, Dr. Rye said.
To investigate HDL’s possible antiinflammatory functions, Dr. Rye’s group used a female Lewis rat model of induced arthritis. The rats received a single intraperitoneal injection of PG-PS, a bacterial cell wall component consisting of peptidoglycan and polysaccharide chains that induces a systemic inflammatory response. All animals exhibited a biphasic inflammatory response after the injection of PG-PS. The acute phase was characterized by joint swelling (rated on a score of 0 to 5). After a brief remission period (Days Seven to Nine following injection), inflammation returned, and entered a chronic phase until Day 21, when the study ended.
Animals were divided into four groups. Rats in the control group were given IV saline injections at the acute and chronic phases. The other three groups of animals received IV injections of apoA-1 (the main apolipoprotein in HDL) either alone or in combination with saline at different time periods: a single treatment during either the acute or chronic phases of inflammation, or, as in group 4, injections of only apoA-1 during both the acute and chronic phases. Regardless of when the apoA-1 was administered, the injection produced a markedly reduced inflammatory response. The team also looked at T-cell and monocyte activation in all groups of animals. They found that, irrespective of the timing of the apoA-1 injection, the T-cell and monocyte counts were reduced nearly to baseline levels by the end of the experimental period (21 days from injection of PG-PS).
From these preliminary results, the team concluded that apoA-1 inhibits PG-PS–induced T-cell activation and cytokine production, and that it is effective in inhibiting joint inflammation in the Lewis rat. This study is part of an ongoing project, Dr. Rye noted, and her team has retained plasma and tissue samples from the animals to further test the levels of a list of chemokines to see whether the results hold. “We’re going to be looking much more closely at these markers and see if we can identify some of the pathways that are involved in mediating these effects,” she said.
Linking Cholesterol Transport and Inflammation
Uwe J. F. Tietge, MD, PhD, professor of pediatrics at the Center for Liver, Digestive, and Metabolic Diseases at the University Medical Center Groningen, The Netherlands, also spoke at the session. In his talk entitled, “Liver X Receptor Signaling at the Crossroads between Immunity and Cholesterol Homeostasis,” Dr. Tietge first summarized the large body of work on reverse cholesterol transport (RCT), a process mediated by LXR transcription. Liver X receptors (LXRs) function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types.2 When LXRs are activated, they induce expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. “Globally,” noted Dr. Tietge, “LXR activation coordinates the response to eliminate cholesterol from the body.” LXRα, the alpha isoform, is mainly expressed in the liver, intestine, kidney, adrenals, adipose tissue, and macrophages. The beta isoform of LXR (LXRβ) is more ubiquitously expressed.
LXR activation also increases the expression of antiinflammatory genes. The ability of LXRs to integrate metabolic and inflammatory signaling makes them potentially attractive targets for designing interventions in metabolic disease.
Dr. Tietge’s group designed a study, published in Gastroenterology, to explore the relevance of biliary sterol secretion, supposedly the final step in the reverse cholesterol transport pathway.3 By ligating the bile ducts of mice and following the macrophage to feces RCT, they demonstrated that RCT requires biliary cholesterol secretion.
Dr. Tietge also touched on another intriguing aspect of the relationship between cholesterol metabolism and the inflammatory process—namely, that plasma levels of HDL are markedly decreased in acute as well as chronic inflammatory states, such as RA. Knowing that acute inflammation induces changes in HDL composition, his group wanted to address whether LXR activation can improve the inflammation-induced reduction in RCT. The study design, he said, aimed “to test an LXR agonist for the treatment of metabolic alterations as a consequence of inflammation.”
In this 30-hour experiment, mice received an LXR agonist either four hours before or four hours after the inflammatory stimulus LPS was administered. LXR activation increased the reverse cholesterol transport by two-fold in wild-type mice who were given PBS. Also, consistent with previous data, RCT was significantly decreased in mice injected with LPS. Pre-treatment with an LXR agonist reversed this phenotype and increased the RCT to the levels shown in the wild-type mice. In other words, Dr. Tietge concluded, “LXR activation promotes pathways resulting in cholesterol elimination from the body.”
We now know, stated Dr. Tietge, that “LXR can directly increase the expression of antiinflammatory genes, and more importantly, that LXR mediates the transrepression of a large set of genes induced by inflammation.”
Most animal studies have shown antiinflammatory effects of LXR agonists given before or together with an inflammatory stimulus. However, Dr. Tietge noted, this “does not represent a realistic scenario for clinical applications,” because patients present when the inflammatory process has already begun.
And, he pointed out, we cannot simply assume that giving LXR agonists will be the solution to interrupting atherogenesis. Depending on the timing of the treatment, LXR agonists might even act as proinflammatories. When long-term treatment for metabolic disease is considered, exacerbation of inflammatory responses or promotion of tumor growth might occur, further limiting the applicability of LXR agonists for this indication.
Dr. Tietge concluded his talk by offering some perspectives on the directions that future research might take. For instance, more research is required on the timing of LXR agonist administration, especially in the context of LXR expression and coactivator/corepressor recruitment. It also will be necessary to further understand the contribution of potential differential effects of LXR isoforms and specific coactivators or corepressor complexes. Armed with this knowledge, researchers will be able to design more efficient therapeutic strategies targeting this promising pathway.
Gretchen Henkel is a freelance journalist based in California.
References
- Carpintero R, Gruaz L, Brandt KJ, et al. HDL interferes with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production. PLoS One. 2010; 5:e11869.
- Hong E, Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev. 2008;18:461-467.
- Nijstad N, Gautier T, Briand F, et al. Biliary sterol secretion is required for functional reverse cholesterol transport in mice. Gastroenterology, 2010 [epub ahead of print].
