title: Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.
abstract: Expression levels of Notch signaling molecules are increased in synovium from patients with rheumatoid arthritis (RA). However, it is not known which cell type(s) in RA synovium have Notch activation or if they play a pathogenetic role in RA. Here, we used Hes1-GFP/TNF-transgenic (TNF-Tg) mice to investigate the role of cells with active Notch signaling (GFP+) in RA. The number of GFP+ cells was significantly increased in synovium in Hes1-GFP/TNF-Tg mice and about 60% of them were F4/80+ macrophages expressing the inflammatory macrophage (M1) marker. TNF-Tg mice transplanted with Hes1-GFP/TNF-Tg bone marrow (BM) had significantly more GFP+ cells in their synovium than in BM. Intraarticular injection of Hes1-GFP/TNF-Tg or Hes1-GFP+ BM macrophages into WT and TNF-Tg mice showed the highest synovial GFP+ cells in the TNF-Tg mice that received Hes1-GFP/TNF-Tg cells. Thapsigargin (THAP), a Notch inhibitor, decreased TNF-induced M1 and increased M2 numbers and reduced joint lesion, synovial M1s, and GFP+ cells in Hes1-GFP/TNF-Tg mice. THAP did not affect M1s from mice carrying a constitutively active Notch1. Thus, the main cells with activated Notch signaling in the inflamed synovium of TNF-Tg mice are M1s derived from BM and targeting them may represent a new therapeutic approach for patients with inflammatory arthritis. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Hengwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.|Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Allergy/Immunology and Rheumatology Division, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Yahui Grace
authors.initials: YG
authors.lastname: Chiu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Allergy/Immunology and Rheumatology Division, University of Rochester Medical Center, Rochester, NY, USA.|Center for Musculoskeletal Research (CMSR), University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Ritchlin
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kiernan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.|Center for Musculoskeletal Research (CMSR), University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.|Center for Musculoskeletal Research (CMSR), University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007596:Joints / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch
keywords: BONE RESORPTION; HES1; HES1-GFP; M1/M2 POLARIZATION; MACROPHAGE; NOTCH; RHEUMATOID ARTHRITIS; THAPSIGARGIN; TNF; TNF-TG