Enteric Toll-like receptor 7 stimulation causes acute exacerbation in lupus-susceptible mice

• Published in: Clinical rheumatology 2023-04, Vol.42 (4), p.1185-1194
• Main Authors: 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, Hashimoto, Motomu
• Format: Article
• Language: English
• Subjects: Animals; Antinuclear antibodies; Autoimmune diseases; Dendritic Cells; Effector cells; Enzyme-linked immunosorbent assay; Flow cytometry; Imiquimod; Imiquimod - metabolism; Immunoglobulin G; Immunoregulation; Kidneys; Kinases; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocytes; Lymphocytes B; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Mice; Mutation; Oral administration; Original Article; Plasma cells; Rheumatology; Splenomegaly; Systemic lupus erythematosus; TLR7 protein; Toll-Like Receptor 7 - metabolism; Toll-like receptors; ZAP-70 protein
• ISSN: 0770-3198; 1434-9949
• DOI: 10.1007/s10067-022-06467-7

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.