Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis

JCI Insight. 2018 Apr 5;3(7):e98864. doi: 10.1172/jci.insight.98864.

Abstract

Mesenchymal TNF signaling is etiopathogenic for inflammatory diseases such as rheumatoid arthritis and spondyloarthritis (SpA). The role of Tnfr1 in arthritis has been documented; however, Tnfr2 functions are unknown. Here, we investigate the mesenchymal-specific role of Tnfr2 in the TnfΔARE mouse model of SpA in arthritis and heart valve stenosis comorbidity by cell-specific, Col6a1-cre-driven gene targeting. We find that TNF/Tnfr2 signaling in resident synovial fibroblasts (SFs) and valvular interstitial cells (VICs) is detrimental for both pathologies, pointing to common cellular mechanisms. In contrast, systemic Tnfr2 provides protective signaling, since its complete deletion leads to severe deterioration of both pathologies. SFs and VICs lacking Tnfr2 fail to acquire pathogenic activated phenotypes and display increased expression of antiinflammatory cytokines associated with decreased Akt signaling. Comparative RNA sequencing experiments showed that the majority of the deregulated pathways in TnfΔARE mesenchymal-origin SFs and VICs, including proliferation, inflammation, migration, and disease-specific genes, are regulated by Tnfr2; thus, in its absence, they are maintained in a quiescent nonpathogenic state. Our data indicate a pleiotropy of Tnfr2 functions, with mesenchymal Tnfr2 driving cell activation and arthritis/valve stenosis pathogenesis only in the presence of systemic Tnfr2, whereas nonmesenchymal Tnfr2 overcomes this function, providing protective signals and, thus, containing both pathologies.

Keywords: Arthritis; Autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve Stenosis / complications
  • Aortic Valve Stenosis / genetics
  • Aortic Valve Stenosis / immunology*
  • Aortic Valve Stenosis / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Fibroblasts
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / immunology*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Signal Transduction / immunology*
  • Spondylarthritis / complications
  • Spondylarthritis / genetics
  • Spondylarthritis / immunology*
  • Spondylarthritis / pathology
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Receptors, Tumor Necrosis Factor, Type II
  • Tnf protein, mouse
  • Tnfrsf1b protein, mouse
  • Tumor Necrosis Factor-alpha

Grants and funding

M.S.