Research ArticleRheumatoid Arthritis

HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaau8587
DOI: 10.1126/scitranslmed.aau8587

Malleable and manipulative macrophages

Macrophages play a critical role in rheumatoid arthritis (RA), an autoimmune disease characterized by chronic joint inflammation. Kuo et al. used single-cell RNA sequencing to identify a subset of inflammatory macrophages within human RA joints that promoted synovial fibroblast invasiveness. Testing several approved treatments for RA in ex vivo explants revealed that most drugs target inflammatory macrophages but may not resolve pathologic response. An epidermal growth factor receptor inhibitor used to treat cancer could block macrophage-fibroblast cross-talk in RA samples. This study helps elucidate macrophage phenotypes and macrophage-fibroblast cross-talk in RA, with implications for therapeutic targeting.


Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor–dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.

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