101. Enteric Toll-like receptor 7 stimulation causes acute exacerbation in lupus-susceptible mice.
- Author
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Takase, Yudai, Shirakashi, Mirei, Nishida, Yuri, Katsushima, Masao, Onizawa, Hideo, Hiwa, Ryosuke, Tsuji, Hideaki, Kitagori, Koji, Akizuki, Shuji, Onishi, Akira, Nakashima, Ran, Murakami, Kosaku, Yoshifuji, Hajime, Tanaka, Masao, Tsuruyama, Tatsuaki, Morinobu, Akio, and Hashimoto, Motomu
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B cells , *TOLL-like receptors , *DISEASE exacerbation , *T helper cells , *SYSTEMIC lupus erythematosus , *REGULATORY T cells , *ORAL drug administration - Abstract
Autoimmune diseases are often accompanied by acute exacerbation. However, the mechanism underlying systemic lupus erythematosus (SLE) flares remains unclear. We investigated whether short-term enteric Toll-like receptor 7 (TLR7) stimulation can exacerbate SLE using B6SKG mice, which spontaneously develop SLE due to a mutation in the zeta‒chain‒associated protein kinase 70 (Zap70) gene. Imiquimod (IMQ) or phosphate-buffered saline (PBS) were orally administered on B6WT and B6SKG mice every other day for 2 weeks. SLE exacerbation was assessed via fluorescent immunohistochemical staining of glomeruli for IgG and C3, hematoxylin and eosin staining of kidneys, and enzyme-linked immunosorbent assay for antinuclear antibody (ANA). Flow cytometry was used to evaluate germinal center B cells (GCBs), plasma cells, follicular helper T cells (Tfhs), regulatory T cells (Tregs), effector T cells (Th1s and Th17s), plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and macrophages (Mφs) in spleens. Oral administration of IMQ every other day for 2 weeks resulted in exacerbation of splenomegaly, increased IgG and C3 deposition in glomeruli, and increased ANA production in the B6SKG IMQ (SKG-IMQ) group compared to the B6SKG PBS (SKG-PBS) group; the percentages of GCBs, plasma cells, Tfhs, Th1s, pDCs, and Mφs were also increased in the SKG-IMQ group. Splenomegaly, IgG, and C3 deposition in glomeruli, and the percentages of GCBs, plasma cells, Tfhs, and Th1s were enhanced in SKG-IMQ mice compared with B6SKG mice topically treated with IMQ (SKG-ear-IMQ). Oral TLR7 stimulation in a Zap70 genetic mutation background can cause acute exacerbations of SLE. Key Points • The mechanism of SLE flares is not well understood. • We have created a model that causes short-term SLE exacerbations in mice with a genetic background. • IMQ administered orally causes more SLE in mice than transdermally. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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