High-density lipoprotein (HDL) normally serves as an ally in the fight against inflammation, but in patients with rheumatoid arthritis (RA) that that function backfires, turning “friendly HDL” into an inflammatory agent.
Although people with RA still receive the benefit of HDL’s cholesterol efflux function, researchers suspect changes in HDL and its cargo may be promoting the excess inflammation and accelerated atherosclerosis seen in these patients.
To better understand how HDL is altered in RA, Vanderbilt University Medical Center rheumatologist Michelle Ormseth, M.D., M.S.C.I., and her team set out to characterize HDL-miRNA, the cargo that HDL delivers to cells. Their findings were published in Arthritis & Rheumatology in May 2024.
“To our knowledge, this is the first study to examine HDL-miRNA and its effect on inflammation in patients with RA,” Ormseth said. “We demonstrated that HDL, which is thought to be cardioprotective, is abnormal in RA, and we characterized how it is abnormal.”
“We demonstrated that HDL, which is thought to be cardioprotective, is abnormal in RA and characterized how it is abnormal.”
Heightened Risks
In healthy individuals, HDL plays a vital role in cholesterol efflux, LDL oxidation, and delivering cholesterol to the liver for elimination. However, people with RA have significantly higher rates of atherosclerosis, along with accompanying higher risks of heart attack and death, which are strongly associated with dysfunctional inflammatory processes.
Researchers grapple with what is called the lipid paradox: Why do people with RA, who generally have equivalent HDL levels and slightly lower LDL levels than non-RA patients, have such high rates of cardiovascular disease?
To address this, researchers are now focused on disease-induced dysregulation in lipoprotein function, not aberrations in its quantity. Ormseth and Vanderbilt colleague Kasey C. Vickers, Ph.D., who originally discovered that HDL transports small RNAs from one cell to another to alter cellular function, have been on a quest to learn whether, how and why HDL’s miRNA cargo is altered in patients with RA.
Associations Probed
Ormseth’s team had previously demonstrated an association between alterations in miRNAs with RA disease activity and coronary atherosclerosis. And, how miRNAs modulate inflammation in the synovial joint. In this new study, they tested the hypothesis that alterations in the HDL-miRNA cargo are a catalyst for proinflammatory HDL.
To probe this, Ormseth enrolled 60 study participants: 30 with low to moderate RA disease activity, and 30 without RA. The groups had roughly equivalent HDL and other lipid panel measurements.
More miR-1246 in HDL
The researchers found an abundance of miR-1246 in HDL from patients with RA compared to those without. They also found that HDL delivered the microRNA to macrophages which are important in mediating disease in the RA synovium and in the atherosclerotic plaque.
HDL, bound with miR-1246, moves through the joints and vessel walls to key cells, where it decreases production of the anti-inflammatory DUSP3, an upstream dephosphorylating protein. DUPSP3 regulates the expression of the inflammatory interleukin-6 (IL-6), a cytokine that promotes both RA and cardiovascular disease.
The blunted expression of DUSP3 in RA helps explain how HDL goes from friend to foe. In fact, the researchers found that HDL-mediated delivery of miR-1246 increases IL-6 expression 43-fold. HDL-miR-1246 levels were about twice as high in RA patients compared to healthy participants and about twice as high in those RA patients with active disease state compared to those in remission.
“It is unclear which cells or conditions contributed to the increased miR-1246 cargo binding to HDL in RA patients, but we found that HDL delivers a high volume of miR-1246 to the macrophages, which decreases DUSP3. This, in turn, enables higher expression of the inflammatory cytokine IL-6,” Ormseth said.
Toward Stocking the Arsenal
Disease-modifying antirheumatic drugs, including biologics developed over the past two decades, have gone a long way toward relegating corticosteroids. However, none of these drugs are without side effects, and some drugs increase cardiovascular disease despite controlling inflammation.
“We saw how HDL-miRNA is altered in RA, having the net effect of blunting HDL’s natural anti-inflammatory properties, and we found that DUSP3 is a direct target of miR-1246,” the researcher said.
So, it might be that inhibiting miR-1246, thus protecting the function of DUSP3, will decrease inflammatory response and help preserve cardiovascular and joint health.
“A drug that enables healthy HDL function would likely have fewer side effects because it could target inflammation without dramatic effects on the immune system function,” she added.
Next will come in vivo studies that mirror these lab studies, and subanalyses of the mechanisms observed.
“We want to look at the HDL transport into the joint itself. Some of the work we’re doing now is looking at the delivery of HDL-1246 to the synovial fibroblasts, which also are important to the joint disease of RA,” she said.
“We know macrophages play a big role in these disease processes, but we want to also look at other cell types, as well as circulation of HDL into the joint, as a potential delivery mechanism for new drugs.”
