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• Research Paper Volume 11, Issue 19 pp 8664-8680

  Decreased RIPK1 expression in chondrocytes alleviates osteoarthritis via the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop

  Relevance score: 8.583199

  Shuang Liang, Zheng-Gang Wang, Zhen-Zhen Zhang, Kun Chen, Zheng-Tao Lv, Yu-Ting Wang, Peng Cheng, Kai Sun, Qing Yang, An-Min Chen

  Keywords: RIPK1, TRIF, MYD88, TRAF2, osteoarthritis

  Published in Aging on October 11, 2019

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  Osteoarthritis (OA) is the most common degenerative joint disease and involves the loss of articular cartilage integrity, formation of articular osteophytes, remodeling of subchondral bone, and synovitis. Knockdown of receptor interacting serine/threonine kinase (RIPK) 1 leads to anti-inflammatory and anti-apoptotic effects. However, the involvement of RIPK1 in the pathogenesis of OA is unclear. Here, we evaluated the effect of RIPK1 on chondrocytes and elaborated the underlying molecular mechanism. Knockdown of RIPK1 protected chondrocytes against inflammation and apoptosis induced by interleukin (IL)-1β in vitro and in vivo. RIPK1 was required for myeloid differentiation primary response 88 (MyD88)- and TIR-domain-containing adapter-inducing interferon b (TRIF)-mediated production of matrix metalloproteinases (MMPs) in OA. Moreover, overexpression of RIPK1 promoted the expression of tumor necrosis factor receptor-associated factor 2 (TRAF2), which blocked the expression and phosphorylation of RIPK1. Upregulation of TRAF2 decreased the expression of TRIF, MyD88, and MMPs in chondrocytes. Furthermore, knockdown of RIPK1 blocked activation of the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. In summary, knockdown of RIPK1 alleviated OA in a manner mediated by the TRIF/MyD88-RIPK1-TRAF2 negative feedback loop and activation of the NF-κB and JNK signaling pathways.

  

  The phosphorylation level of RIPK1 is increased in mouse knee articular cartilage. (A, B) Safranin O/Fast Green-stained sagittal-plane images of tibial and femoral cartilage from the sham and destabilized medial meniscus (DMM) groups; the Osteoarthritis Research Society International (OARSI) score was significantly increased in the DMM group (n = 10); scale bar = 200 μm. (C, D) Representative hematoxylin and eosin (HE)-stained images and synovial inflammation scores in the sham and DMM groups (n = 10); scale bar = 400 μm. (E, F) Western blots and quantitative data of p-RIPK1 in the sham and DMM groups. The experiments were repeated three times independently. Columns represent means ± SD. **p < 0.01.

  
  
  

  

  Knockdown of receptor interacting serine/threonine kinase (RIPK) 1 attenuates cartilage degeneration in vivo. (A, B) Immunohistochemical staining of RIPK1 in mice transfected with Ad-NC and Ad-shRIPK1 (n = 10); scale bar = 200 μm. (C, D) Safranin O/Fast Green-stained articular cartilage; the degree of cartilage degeneration was evaluated by calculating the OARSI score (n = 10); scale bar = 200 μm. (E, F) Immunohistochemical staining of matrix metalloproteinases (MMPs; n = 10); scale bar = 200 μm. (G, H) Representative HE-stained images and synovial inflammation scores (n = 10); scale bar = 200 μm. Columns represent means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  
  
  

  

  Knockdown of RIPK1 inhibits interleukin (IL)-1β–induced production of catabolic enzymes and proinflammatory cytokines in vitro. (A, B) Representative western blots and quantitative data of RIPK1 and p-RIPK1 in chondrocytes transfected with Ad-shRIPK1 and Ad-RIPK1. (C, D) Knockdown of RIPK1 reduced the IL-β–induced expression of MMPs in chondrocytes. (E, F) Overexpression of RIPK1 promoted the IL-β–induced expression of MMPs in chondrocytes. (G) Enzyme-linked immunosorbent assay (ELISA) of the tumor necrosis factor (TNF)-α level in culture supernatants. (H, I) Western blots and quantitative data of p-RIPK1 in chondrocytes treated with IL-1β. The experiments were repeated three times independently. Columns represent means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  
  
  

  

  RIPK1 potentiates TIR-domain-containing adapter-inducing interferon b (TRIF)- and myeloid differentiation primary response 88 (MyD88)-dependent IL-β–induced inflammation. (A, B) Western blots and quantitative data of TRIF and MyD88 in chondrocytes transfected with Ad-shRIPK in the presence and absence of IL-1β. © Western blots of TRIF and MyD88 in chondrocytes transfected with si-TRIF or si-MyD88. (D, E) Western blots and quantitative data of MMPs in chondrocytes transfected with si-TRIF or si-MyD88 in the presence and absence of IL-1β. (F, G) Western blots and quantitative data of MMPs in chondrocytes incubated with poly (I:C) or Pam3CSK4 in the Ad-shRIPK and Ad-NC groups. (H, I) Western blots and quantitative data of MMPs in chondrocytes transfected with Ad-shRIPK adenovirus in the si-TRIF and si-MyD88 groups. (J, K) Western blots and quantitative data of p-RIPK1 in chondrocytes treated with IL-1β in the si-TRIF and si-MYD88 groups. The experiments were repeated three times independently. Columns represent means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  
  
  

  

  TRAF2 regulates RIPK1-mediated inflammation. (A, B) Western blots and quantitative data of TRAF2 in chondrocytes transfected with Ad-shRIPK and Ad-RIPK1 in the presence and absence of IL-1β. © TRAF2 expression determined by immunofluorescence staining. Scale bar = 50 μm. (D, E) Western blots and quantitative data of p-RIPK1 and RIPK1. (F, G) Western blots and quantitative data of TRIF, MYD88, and MMPs. The experiments were repeated three times independently. Columns represent means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  
  
  

  

  RIPK1 kinase-mediated osteoarthritis is dependent on apoptosis but not mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis. (A, B) Western blots and quantitative data of p-MLKL. (C, D) Immunohistochemical staining of p-MLKL in the normal and DMM groups (n = 10); scale bar = 200 μm. (E, F) Western blots and quantitative data of MMPs. (G, H) Cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) levels in mouse chondrocytes treated as above. The experiments were repeated three times independently. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

  
  
  

  

  Knockdown of RIPK1 protects chondrocytes against apoptosis in vitro and in vivo. (A, B) Transferase dUTP nick-end labeling (TUNEL)-stained mouse chondrocytes treated as above; scale bar = 200 μm. (C, D) TUNEL-stained paraffin-wax sections of articular cartilage. Red fluorescence, apoptotic cells; blue fluorescence, nuclei (n = 10). Scale bar = 400 μm. The experiments were repeated three times independently. Columns represent means ± SD. ***p < 0.001, ****p < 0.001.

  
  
  

  

  c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) are involved in RIPK1-mediated inflammation. (A, B) Expression levels of p-JNK, p-IKBα, and p-P65 in chondrocytes. The experiments were repeated three times independently. Columns represent means ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. © Schematic of the TIR-domain-containing adapter-inducing interferon b (TRIF)/MYD88-RIPK1-tumor necrosis factor receptor-associated factor 2 (TRAF2) feedback loop and activation of the NF-κB and JNK signaling pathways in OA.

  
  
  

• Research Paper pp undefined-undefined

  Myeloid-specific knockout of Notch-1 inhibits MyD88- and TRIF-mediated TLR signaling pathways by regulating oxidative stress-SHP2 axis, thus restraining aneurysm progression

  Relevance score: 5.4536967

  Yu Li, Ailin Guo, Jianlei Liu, Lijuan Tang, Lide Su, Zonghong Liu

  Keywords: abdominal aortic aneurysm, Notch1, macrophages, oxidative stress, SHP2, MyD88/TRIF/NF-κB signaling pathway

  Published in Aging on Invalid Date

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  Objective: Notch-1 is a signal regulatory protein with extensive effects in myeloid cells, but its role in aneurysms remains to be fully clarified. In this study, therefore, the aneurysm mouse model with myeloid-specific knockout of Notch-1 was established to observe the role of Notch-1 in aneurysm progression.

  Methods and Results: The effect of Notch-1 was assessed by pathological staining and Western blotting. It was found that after myeloid-specific knockout of Notch-1 in the aneurysm mouse model, the area of aneurysms and the macrophage infiltration were significantly reduced, the damage to arterial elastic plates was significantly relieved, and the oxidative stress level significantly declined. The results of Western blotting showed that after myeloid-specific knockout of Notch-1, the levels of oxidative stress-related proteins p22 and p47 in aneurysm tissues significantly declined, accompanied by a significant increase in the protein level of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2). In addition, the levels of phosphorylated myeloid differential protein-88 (MyD88), TIR domain-containing adaptor-inducing interferon-β (TRIF) and nuclear factor-κB (NF-κB), and inflammatory cytokines interferon-γ (IFN-γ), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) also significantly decreased after myeloid-specific knockout of Notch-1. Following myeloid-specific knockout of Notch-1, the phagocytic capacity of macrophages was enhanced by promoting the SHP2 signaling pathway.

  Conclusion: Notch-1 in monocytes/macrophages can activate the Toll-like receptor (TLR)-mediated inflammatory and stress responses by activating oxidative stress and inhibiting the SHP2 protein expression, thus facilitating aneurysm progression.