Cathepsin B Regulates the Appearance and Severity of Mercury-Induced Inflammation and Autoimmunity

Abstract

Susceptibility and resistance to systemic autoimmunity are genetically regulated. This is particularly true for murine mercury-induced autoimmunity (mHgIA) where DBA/2J mice are considered resistant to disease including polyclonal B cell activation, autoantibody responses, and immune complex deposits. To identify possible mechanisms for the resistance to mHgIA, we exposed mHgIA sensitive B10.S and resistant DBA/2J mice to HgCl2 and assessed inflammation and pro-inflammatory responses at the site of exposure and subsequent development of markers of systemic autoimmunity. DBA/2J mice showed little evidence of induration at the site of exposure, expression of proinflammatory cytokines, T cell activation, or autoantibody production, although they did exhibit increased levels of total serum IgG and IgG1. In contrast B10.S mice developed significant inflammation together with increased expression of inflammasome component NLRP3, proinflammatory cytokines IL-1β, TNF-α, and IFN-γ, hypergammaglobulinemia, splenomegaly, CD4(+) T-cell activation, and production of autoantibodies. Inflammation in B10.S mice was associated with a selective increase in activity of cysteine cathepsin B but not cathepsins L or S. Increased cathepsin B activity was not dependent on cytokines required for mHgIA but treatment with CA-074, a cathepsin B inhibitor, led to transient reduction of local induration, expression of inflammatory cytokines, and subsequent attenuation of the systemic adaptive immune response. These findings demonstrate that sensitivity to mHgIA is linked to an early cathepsin B regulated inflammatory response which can be pharmacologically exploited to abrogate the subsequent adaptive autoimmune response which leads to disease.

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

“…Mercury exposure of human neutrophil granulocytes also induces the formation of neutrophil extracellular traps providing another source of TLR agonists (84). These studies are consistent with our observation that mercury exposure induces a localized inflammatory response (85) regulated in part by cathepsin B (61) which is known to be involved in TLR responses (86, 87). Furthermore, the reported finding that exposure of T cells to mercury induces MHC class II-dependent cytokine production and proliferation in vitro only in the presence of antigen-presenting cells (88) is consistent with mercury generating TLR ligands that activate cells to present self-antigens.…”

“…Anti-nuclear Abs (ANAs) were determined by ELISA per manufacturer’s instructions (Inova Diagnostics, San Diego CA) or indirect immunofluorescence as described (61). Briefly, for the latter, HEp-2 cells on glass slides (Inova) were incubated with serum diluted 1/100 and then 1/200 dilution of Alexa Fluor 488-conjugated goat anti-mouse IgG (H&L) (Molecular Probes, Carlsbad, CA).…”

“…ANAs were scored for intensity (0–4+ scale) and pattern under blinded conditions. ELISAs were used to quantitate anti-chromatin (61)(62), ENA5 (Sm, RNP, SS-A/Ro, SS-B/La, Scl70) (Inova Diagnostics, San Diego, CA), anti-DNA, serum IgG (Immunology Consultants Laboratory, Inc, Newburg, OR)(61)(63). A mouse reference sera (Bethyl Laboratories, Montgomery, TX) was used to generate the standard curve (800–0.04 ng/ml).…”

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

“…gov/ gene/ 1508) encodes a lysosomal cysteine proteinase (cathepsin B) that plays various roles in protein turnover and cell processes and it has also been implicated in autoimmunity and arthritis. [39][40][41] Cathepsin B was shown to regulate various immune functions; for example, persistence of memory T cells, antigen-presenting function of dendritic cells, monocyte and macrophage necrosis/necroptosis and TLR signalling. [42][43][44][45][46] The publicly available data on human monocytes and lymphoblastoid cell lines (see online supplementary table S3) have suggested cell type-specific effects/functions of the 8p23 SNPs as also supported by a recent BLK study.…”

Effects of Intracellular Process on the Therapeutic Activation of Nanomedicine

“…So, cathepsin B has been described as an essential mediator in TNFα-mediated apoptosis [65,66]. For instance, hepatocytes from cathepsin B knockout mice are relatively resistant to TNF-α-induced apoptosis [67], for cathepsin B participates in TNF-α-induced, caspase-independent cell death of WEHI-S cells [68]. Ceramide generated by the lysosomal sphingomyelinase can trigger the proteolytic autoactivation of cathepsin D [69].…”