Editors' ChoiceRheumatoid Arthritis

Macrophages take rheumatoid arthritis up a “Notch”

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Science Translational Medicine  29 Mar 2017:
Vol. 9, Issue 383, eaan3022
DOI: 10.1126/scitranslmed.aan3022


Notch signaling in bone marrow–derived inflammatory macrophages is central to synovial inflammation seen in rheumatoid arthritis, representing a promising future therapeutic target.

Inflammation and inflammatory cells are known to play a central role in rheumatoid arthritis (RA). Joint disease in RA has been characterized by macrophage infiltration, lymphocyte migration, synoviocyte proliferation, and joint destruction. Although human studies have shown increased expression of Notch signaling molecules in the synovium from patients with RA, the role of Notch signaling and different macrophage phenotypes in RA has only recently been elucidated.

A study by Sun and colleagues establishes a positive relationship between Notch signaling and RA-induced joint destruction, identifying a specific cell type (macrophage) and phenotype (inflammatory M1 macrophage) that exacerbates the disease. Using Notch reporter mice with an RA-inducing mutation, the authors examined which cells had Notch activation in the arthritic joint synovium by flow cytometry and immunostaining. After identifying the M1 inflammatory macrophage population, the authors further demonstrated the origin of the macrophages as bone marrow–derived. Bone marrow–derived macrophages in the RA mutant mice were shown to have a higher potential to adopt the M1 phenotype. Furthermore, the inflammatory microenvironment increased macrophage Notch expression. Treatment with thapsigargin, a Notch signaling inhibitor, decreased M1 macrophage polarization, increased M2 polarization, and decreased RA joint damage.

This study changes the previous paradigm that macrophage renewal in RA occurs independent of the bone marrow. The bone marrow transplantation studies by Sun et al. indicate that donor-derived bone marrow cells are recruited to the inflamed synovium. Importantly, this study also demonstrates the key signaling pathway, Notch, which is activated in macrophages upon their arrival within the synovium. Based on these findings, researchers now have a potential cell (macrophage) and potential target (Notch signaling) for which specific therapeutics can be developed. Whether these findings will extend to other autoimmune diseases, osteoarthritis, or traumatic inflammation is yet to be determined. Those working on therapeutic discovery for RA should read closely and take it up a Notch as they develop the next line of therapies.

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