title: 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.
authors.affiliation: *Department of Ophthalmology, School of Medicine, Duke University, 2351 Erwin Road, Durham, North Carolina 27710, Department of Surgery and Center for Investigations of Health and Education Disparities, School of Medicine, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, California 92093-0739 and Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Toomey
authors.affiliation: *Department of Ophthalmology, School of Medicine, Duke University, 2351 Erwin Road, Durham, North Carolina 27710, Department of Surgery and Center for Investigations of Health and Education Disparities, School of Medicine, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, California 92093-0739 and Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
authors.forename: David M
authors.initials: DM
authors.lastname: Cauvi
authors.affiliation: *Department of Ophthalmology, School of Medicine, Duke University, 2351 Erwin Road, Durham, North Carolina 27710, Department of Surgery and Center for Investigations of Health and Education Disparities, School of Medicine, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, California 92093-0739 and Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
authors.forename: John C
authors.initials: JC
authors.lastname: Hamel
authors.affiliation: *Department of Ophthalmology, School of Medicine, Duke University, 2351 Erwin Road, Durham, North Carolina 27710, Department of Surgery and Center for Investigations of Health and Education Disparities, School of Medicine, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, California 92093-0739 and Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Ramirez
authors.affiliation: *Department of Ophthalmology, School of Medicine, Duke University, 2351 Erwin Road, Durham, North Carolina 27710, Department of Surgery and Center for Investigations of Health and Education Disparities, School of Medicine, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, California 92093-0739 and Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 mpollard@scripps.edu.
authors.forename: K Michael
authors.initials: KM
authors.lastname: Pollard
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D003872:Dermatitis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D004151:Dipeptides / Q000494:pharmacology; D004198:Disease Susceptibility / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D008627:Mercuric Chloride / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004151:Dipeptides; D007074:Immunoglobulin G; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D008627:Mercuric Chloride; D002401:Cathepsin B
keywords: T-cell activation; autoimmunity; cathepsin B.; cytokines; inflammation; mercuric chloride