Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts

Eur J Immunol. 2017 Dec;47(12):2101-2112. doi: 10.1002/eji.201646788. Epub 2017 Sep 22.

Abstract

The IL-1 family member IL-36α has proinflammatory and pathogenic properties in psoriasis. IL-36α binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36α. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36α-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36α and stimulation increased IL-36α in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36α by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36α-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints.

Keywords: B cell; IL-36R; MAPK signaling; Plasma cell; Synovial fibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Gene Expression / immunology
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology
  • Jurkat Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NIH 3T3 Cells
  • Plasma Cells / immunology*
  • Plasma Cells / metabolism
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / immunology*
  • Receptors, Interleukin-1 / metabolism
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology*
  • Synovial Membrane / metabolism

Substances

  • Cytokines
  • Interleukin-1
  • Receptors, Interleukin-1
  • interleukin 1F6, mouse
  • interleukin-36 receptor, mouse