OBJECTIVE: To examine whether topical treatment of wild-type mice with Toll-like receptor 7 (TLR-7) agonists leads to lupus-like autoimmunity. METHODS: Wild-type FVB/N, BALB/c, and C57BL/6 mice were treated with the topical TLR-7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and fluorescence-activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti-PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease-causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR-7- and TLR-9-deficient mice were used to validate the role of TLR-7. RESULTS: Wild-type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to double-stranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon-α-stimulated gene, was up-regulated in the organs of imiquimod-treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR-7-deficient mice, but not TLR-9-deficient mice, were protected against autoimmunity. CONCLUSION: This protocol provides a novel model of inducible systemic lupus erythematosus in wild-type mice and underscores the skin as the primary organ that allows TLR-7 agonists to induce SLE.
OBJECTIVE: To examine whether topical treatment of wild-type mice with Toll-like receptor 7 (TLR-7) agonists leads to lupus-like autoimmunity. METHODS: Wild-type FVB/N, BALB/c, and C57BL/6 mice were treated with the topical TLR-7 agonist imiquimod or R848 administered to the ear 3 times weekly. During treatment, the mice were monitored for serum autoantibody and creatinine levels as well as histopathology of the kidneys, spleens, livers, hearts, and skin. Immunologic abnormalities were analyzed by immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and fluorescence-activated cell sorting. The role of plasmacytoid dendritic cells (PDCs) in the development of autoimmune disease was validated by in vivo treatment with an anti-PDC antibody. Diseased mice underwent ultraviolet B irradiation, to evaluate skin photosensitivity. The disease-causing effect of topical application of imiquimod was compared with that of systemic (intraperitoneal) administration. TLR-7- and TLR-9-deficient mice were used to validate the role of TLR-7. RESULTS: Wild-type mice of different genetic backgrounds developed systemic autoimmune disease following 4 weeks of topical treatment with imiquimod or R848, with elevated levels of autoantibodies to double-stranded DNA and multiple organ involvement, including glomerulonephritis, hepatitis, carditis, and photosensitivity. Expression of Ifna and Mx1, the interferon-α-stimulated gene, was up-regulated in the organs of imiquimod-treated mice. However, disease caused by intraperitoneal injection of imiquimod was less severe than that induced by topical application. In vivo depletion of PDCs by a specific antibody protected mice against the autoimmunity induced by topical administration of imiquimod, suggesting a role of PDCs. Furthermore, TLR-7-deficient mice, but not TLR-9-deficient mice, were protected against autoimmunity. CONCLUSION: This protocol provides a novel model of inducible systemic lupus erythematosus in wild-type mice and underscores the skin as the primary organ that allows TLR-7 agonists to induce SLE.
Authors: Gautam Sule; Basel H Abuaita; Paul A Steffes; Andrew T Fernandes; Shanea K Estes; Craig Dobry; Deepika Pandian; Johann E Gudjonsson; J Michelle Kahlenberg; Mary X O'Riordan; Jason S Knight Journal: J Clin Invest Date: 2021-04-01 Impact factor: 14.808
Authors: Teri M Greiling; Carina Dehner; Xinguo Chen; Kevin Hughes; Alonso J Iñiguez; Marco Boccitto; Daniel Zegarra Ruiz; Stephen C Renfroe; Silvio M Vieira; William E Ruff; Soyeong Sim; Christina Kriegel; Julia Glanternik; Xindi Chen; Michael Girardi; Patrick Degnan; Karen H Costenbader; Andrew L Goodman; Sandra L Wolin; Martin A Kriegel Journal: Sci Transl Med Date: 2018-03-28 Impact factor: 17.956
Authors: Rishi R Goel; Xinghao Wang; Liam J O'Neil; Shuichiro Nakabo; Kowser Hasneen; Sarthak Gupta; Gustaf Wigerblad; Luz P Blanco; Jeffrey B Kopp; Maria I Morasso; Sergei V Kotenko; Zu-Xi Yu; Carmelo Carmona-Rivera; Mariana J Kaplan Journal: Proc Natl Acad Sci U S A Date: 2020-02-24 Impact factor: 11.205