Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Fas lpr Mice

J Immunol. 2017 Mar 1;198(5):1846-1854. doi: 10.4049/jimmunol.1501145. Epub 2017 Jan 16.

Abstract

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those from Faslpr mice showed elevated CatK expression in the glomeruli and tubulointerstitial space. Faslpr mice also showed elevated serum CatK levels. CatK deficiency in Faslpr mice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed to Faslpr mouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmunity
  • Cathepsin K / blood
  • Cathepsin K / deficiency*
  • Cathepsin K / genetics
  • Cathepsin K / physiology*
  • Complement C3 / immunology
  • Glomerulonephritis / immunology
  • Immunoglobulin G / immunology
  • Kidney / immunology
  • Kidney / physiopathology
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / physiopathology*
  • Lupus Nephritis / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Spleen / immunology
  • Spleen / physiopathology
  • T-Lymphocytes, Regulatory / immunology
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology
  • fas Receptor / genetics
  • fas Receptor / immunology

Substances

  • Complement C3
  • Immunoglobulin G
  • Membrane Glycoproteins
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • fas Receptor
  • Cathepsin K