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Sci Transl Med. 2019 May 8;11(491). pii: eaau8587. doi: 10.1126/scitranslmed.aau8587.

HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness.

Author information

1
Graduate Program in Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
2
Computational Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
3
Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA.
4
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Division of Rheumatology and Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
7
Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8
Division of Rheumatology, Immunology, Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
10
Weill Cornell Medical College, New York, NY 10021, USA.
11
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, UK.
12
Department of Computer Science, Universitätstrasse 6, ETH Zürich, 8092 Zürich, Switzerland.
13
Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
14
Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA. donlinl@hss.edu.

Abstract

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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