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

Abstract

Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but it is also inducible under inflammatory conditions. Faslpr mice on a C57BL/6 background develop spontaneous systemic lupus erythematosus (SLE)-like manifestations. While 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 Toll-like receptor-7 (TLR7) proteolytic processing and consequent regulatory T cell (Treg) biology. Elevated TLR7 expression and proteolytic processing in Faslpr mouse kidneys and Treg cells showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+ Treg cells from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared to those from CatK-sufficient mice. In Faslpr mice, repopulation of purified Treg cells from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg cell contents. Treg cells from CatK-deficient mice had significantly more potency than CatK-sufficient Treg cells in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg cell content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.

CD74 Deficiency Mitigates Systemic Lupus Erythematosus–like Autoimmunity and Pathological Findings in Mice

“…Fas lpr mice develop mild lupus-like manifestations after 4 months of age (24), and symptoms become significant when mice reached to 6 to 9 months of age (25, 26). 24-week-old Fas lpr and WT control mice helped test whether development of lupus-like autoimmunity in Fas lpr mice altered CD74 expression.…”

Lysosomes as a therapeutic target

“…In addition, lysosomal cathepsin K was seen to contrib ute to the pathological events that develop in Fas lpr mice, another model of lupus disease, in part through its activity in TLR7 proteolytic processing and subsequent effects on regulatory T cells. Cathepsin K deficiency in Fas lpr mice reduced all kidney pathological manifesta tions (glomerulus and tubulointerstitial scores, glo merulus complement C3 fraction and IgG deposition, chemokine expression and macrophage infiltration) and decreased the levels of potentially pathogenic serum autoantibodies 96 .…”

“…Further studies based on cathepsin S inhibitors should evaluate the clinical safety and utility of treating patients affected by autoimmune and inflammatory diseases 295 . Cathepsin K, which is highly expressed by osteoclasts and very effi ciently degrades type I collagen, the major component of the organic bone matrix, is also a potential target for modulating lysosomal dysfunction in some of the dis orders discussed above, such as SLE 96 . Yet further investi gations with selective cathepsin K inhibitors are required to determine whether this targeted strategy might apply in SLE and other inflammatory conditions in which articular manifestations are a major component (RA, ankylosing spondylitis, psoriatic arthritis and others).…”

Cathepsin K: The Action in and Beyond Bone

“…CatK could play a unique role in autoimmune diseases. Researchers have previously showed that either genetic deficiency or pharmacological inhibition of CatK could suppress the autoimmune inflammation in animals with experimental autoimmune encephalomyelitis and adjuvant-induced arthritis and lupus, respectively (Asagiri et al, 2008;Zhou et al, 2017). In the study by Takayanagi's group, they demonstrated that the lack of CatK activity could affect the innate immune response to pathogen DNA by compromising Toll-like receptors 9 (TLR9) signaling in dendritic cells (DCs), leading to the attenuated induction of T helper 17 cells without affecting the antigenpresenting ability of DCs (Asagiri et al, 2008).…”