Collaborators at the University of Cologne, VIB, Ghent University, the Βiomedical Sciences Research Center Alexander Fleming in Athens, and the University of Tokyo say they have identified a new molecular mechanism causing rheumatoid arthritis.

The scientists found that death of macrophages can trigger the disease. Moreover, they discovered how the protein A20 prevents macrophage death and protects against arthritis. These findings open up new possibilities for the treatment of this debilitating disease, according to the researchers.

Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that affects the joints, causing a painful swelling that eventually results in bone erosion and joint deformity. There is no cure for RA, but the disease progression in most patients can be slowed down with anti-inflammatory drugs. The underlying molecular mechanisms that cause the disease have remained largely unclear. Understanding these mechanisms may help in developing new therapies to treat patients suffering from RA.

The team built upon earlier research at the VIB-UGent Center for Inflammation Research, which demonstrated that the protein A20 suppressed arthritis by preventing inflammation. Now the researchers report in Nature Cell Biology (“A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain”) that the inflammatory response is caused by the fact that macrophages die by a specific inflammation-promoting type of cell death called necroptosis. The scientists were able to prevent the development of RA by blocking necroptosis.

“Deficiency in the deubiquitinating enzyme A20 causes severe inflammation in mice, and impaired A20 function is associated with human inflammatory diseases. A20 has been implicated in negatively regulating NF-κB signaling, cell death, and inflammasome activation; however, the mechanisms by which A20 inhibits inflammation in vivo remain poorly understood. Genetic studies in mice revealed that its deubiquitinase activity is not essential for A20 anti-inflammatory function,” the investigators wrote.

“Here we show that A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis and that this function depends on its zinc finger 7 (ZnF7). We provide genetic evidence that RIPK1 kinase-dependent, RIPK3–MLKL-mediated necroptosis drives inflammasome activation in A20-deficient macrophages and causes inflammatory arthritis in mice. Single-cell imaging revealed that RIPK3-dependent death caused inflammasome-dependent IL-1β release from lipopolysaccharide-stimulated A20-deficient macrophages. Importantly, mutation of the A20 ZnF7 ubiquitin binding domain caused arthritis in mice, arguing that ZnF7-dependent inhibition of necroptosis is critical for A20 anti-inflammatory function in vivo.”

“We [identified] why these macrophages are dying and could demonstrate the importance of a specific part in the protein A20 for the prevention of cell death and RA development,” said Geert van Loo, PhD, group leader at VIB-UGhent.

“We revealed how the particular type of macrophage demise shapes the activation of synovial fibroblasts, a key cell type that orchestrates the destruction of cartilage and bone tissue in RA,” underlined Marietta Armaka, PhD, research group head at BSRC Alexander Fleming.

This study confirms the crucial importance of A20 in the control of inflammation, but now also shows that preventing cell death is a critical anti-inflammatory function of A20 to protect against arthritis, noted Manolis Pasparakis, PhD, head of research and principal investigator, at the Institute for Genetics, University of Cologne. “From a therapeutic perspective, this is a very important finding, since it suggests that drugs inhibiting cell death could be effective in the treatment of RA, at least in a subset of patients where macrophage death could provide the underlying trigger.”

Previous articleHeart Disease Prevention May Be Linked to Rare Gene Mutation
Next articleBladder Drug May Raise Risk of Blocked Arteries, Heart Disease, and Stroke