Macrophages in rheumatoid arthritis split into "inflammation" and "pain" groups

A research team including Researcher Hiroki Mukoyama, Assistant Professor Hitomi Watanabe, Professor Gen Kondoh, and Associate Professor Keiji Hirota at the Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences at Kyoto University, has discovered a new mechanism that triggers chronic inflammation and pain in autoimmune arthritis. They found that inflammatory monocytes traveling from bone marrow transform into two distinct groups within the joints: one responsible for "inflammation" and the other for "pain."

Mukoyama said: "We see patients whose joint inflammation is under control, yet they continue to suffer from pain. By targeting the macrophages found in this study, we hope to develop treatments that improve pain as well as inflammation." The findings were published in Science Advances.

Rheumatoid arthritis is an autoimmune disease that affects 1% of the population, in which immune cells induce inflammation, causing joint pain and swelling. Macrophages are a major source of inflammatory cytokines such as tumor necrosis factor (TNF), play a central role in amplifying and maintaining disease states, and have recently been implicated in pain.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a type of cytokine, was shown from mouse models and clinical trials to be deeply involved in the pathogenesis of arthritis. However, it was not known which cells GM-CSF affected and how it caused inflammation.

The research team thought that GM-CSF might be acting on macrophages in the joints, causing inflammation and pain. In SKG mice lacking the chemokine receptor CCR2 (a mouse model of autoimmune arthritis that exhibits pathology similar to human rheumatoid arthritis), inflammatory monocytes were unable to migrate into the joints, and they had markedly milder arthritis than wild-type SKG mice, indicating that inflammatory monocytes are important in arthritis.

Analysis of the development and differentiation process of joint macrophages revealed that monocytes migrating from the bone marrow, rather than tissue-resident macrophages, are the primary progenitor cells of pathogenic macrophages. Next, by combining CCR2-deficient SKG mice and GM-CSF receptor-deficient SKG mice to block GM-CSF signaling in inflammatory monocytes and macrophages, the researchers found that arthritis almost never developed. This led them to discover that GM-CSF signaling is essential for inflammatory monocytes and macrophages to acquire pathogenicity.

In addition, single-cell RNA sequencing was performed on inflamed joint tissue from mice transplanted with a mixture of bone marrow from wild-type SKG and GM-CSF receptor-deficient SKG mice (mixed bone marrow chimeras). By marking each mouse-derived cell, cells that can and cannot receive GM-CSF signaling can be compared and analyzed in detail.

The results showed that Arg1⁺ macrophages and EpCAM⁺ macrophages were deficient in cells derived from GM-CSF receptor-deficient SKG mice. These macrophages expressed high levels of inflammatory cytokines, and EpCAM⁺ macrophages specifically expressed CCL17, a molecule involved in pain.

While the impact of GM-CSF on joint macrophages was previously unknown, this study revealed for the first time that it is essential for the differentiation of these highly pathogenic macrophage populations with specific functions.

These research results may lead to the development of new treatments for rheumatoid arthritis.

There has been no treatment for rheumatoid arthritis that targets macrophages. By targeting pathogenic macrophages such as the newly discovered Arg1⁺ and EpCAM⁺ macrophages, it may be possible to develop treatments that target not only inflammation but also pain.

The research group plans to continue their work by studying clinical samples taken from human patients during surgery.

Journal Information
Publication: Science Advances
Title: Pathogenic GM-CSF drives functional diversification of inflammatory macrophages in autoimmune arthritis
DOI: 10.1126/sciadv.aec0986