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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.

SUBMITTER: Sun W

PROVIDER: S-EPMC5489377 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.

Sun Wen W Zhang Hengwei H Wang Hua H Chiu Yahui Grace YG Wang Mengmeng M Ritchlin Christopher T CT Kiernan Amy A Boyce Brendan F BF Xing Lianping L

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20170410 7

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+ macroph ...[more]

PMID: 28256007

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Project description:BackgroundGlaucocalyxin B (Gla B) is a type of sesquiterpenoids. At present, there are rare studies on the pharmacological effects and targets of sesquiterpenoids, while multiple sesquiterpenoids have good anti-inflammatory properties. Therefore, in this study, we aimed to investigate the mechanism of Gla B on macrophages and rheumatoid arthritis.MethodsLPS/IFN-γ was used to induce M1 polarization of synovial macrophage (SMG) in vitro, followed by Gla B pretreatment (5 μM and 15 μM). Afterwards, flow cytometry was performed to detect the proportion of M1 cells (F4/80+CD86+), enzyme-linked immunosorbent assay (ELISA) was used to determine the expression levels of M1 cell markers (TNF-α, IL-1β, IL-6, iNOS and IL-12) as well as M2 cell markers (IL-10 and TGF- β1), immunofluorescence (IF) staining was utilized to measure the expression of CD86, the level of ROS was assessed by probe and Western blot was conducted to detect the expression of P65 and p-P65. M1 polarization was detected in SMG cells with P65 silencing after 15 μM Gla B intervention. The culture medium from M1 cell was used to culture cartilage cells in vitro, followed by detection of cartilage cell injury. In animal models, collagen antibodies and LPS were combined to induce RA mouse model. Afterwards, H and E staining was performed to detect pathological changes in mouse joint synovium, safranin O-fast green staining was used to determine cartilage injury, and immunohistochemistry was utilized to detect CD86 and P65 expression. Small molecule-protein docking and co-immunoprecipitation (Co-IP) were used to verify the targeted binding relationship between Gal B and P65.ResultsLPS and IFN-γ could induce M1 polarization in SMG. Gal B could inhibit M1 polarization, decrease the levels of TNF-α, IL-1β, IL-6, iNOS and IL-12, inhibit the expression of P65 and p-P65 while did not affect the expression of IL-10 or TGF-β1. Gal B had no significant effect in SMG cells with P65 silencing. The small molecule-protein docking and Co-IP both showed that Gal B had a targeted binding relationship with P65, and Gal B could inhibit joint injury and inflammation in mice.ConclusionGal B could target the P65 protein. Moreover, Gal B could inhibit the inflammatory injury of articular cartilage in RA by regulating M1 polarization of SMG through inhibiting the NF-κB signaling.

Dataset Information

Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.

Publications

Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.

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