Activation of Toll-like Receptor-7 Exacerbates Lupus Nephritis by Modulating Regulatory T Cells

Abstract

Background: Toll-like receptor-7 (TLR7), which recognizes viral single-stranded RNA, can trigger immune complex glomerulonephritis in experimental lupus erythematosus. However, whether it modulates dendritic cells (DCs) phenotype and regulatory T cells (Treg) function is incompletely understood. Method: Splenocytes and bone marrow DCs were obtained from 5- and 20-week-old female MRL^lpr/lpr mice and C57BL/6 mice. In addition, to understand the response of Treg and DCs to TLR7 ligation in vivo, 16-week-old female MRL^lpr/lpr and C57BL/6 mice were distributed into two groups with or without intraperitoneal injections of TLR7 ligand every other day. Results: After activation with the TLR7 ligand imiquimod in vivo and vitro, DCs from imiquimod-treated MRL/lpr mice showed an altered costimulatory profile, with decreased induction of CD80, CD86, and MHCII expression, comparing to age-matched C57BL/6 control mice. There was no significant difference in the numbers of CD₄⁺CD₂₅⁺Foxp3⁺ cells after TLR7 ligation by imiquimod in MRL^lpr/lpr and control mice. Immunostaining of kidney sections of nephritic MRL/lpr mice revealed that CD11c was expressed in the infiltrated tubulointerstitial cells, and confocal microscopic analysis of renal CD11c⁺MHCII⁺, CD11c⁺CD80⁺, and CD11c^+​CD86⁺ cells showed an immature phenotype with low levels of CD80, CD86, and MHCII in imiquimod-treated MRL/lpr mice. There was no difference in the number of Foxp3 positive cells in kidneys between the imiq‑uimod and vehicle-treated groups. Conclusions: Our results suggest that activation of TLR7 exacerbated lupus nephritis by modulating the abnormally costimulatory phenotype of dendritic cells and functions of Treg in MRL/lpr mice.

Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus

“…To this end, we decided to use an inducible model for lupus in the GF setting and then test whether B. theta monocolonization leads to signs of autoimmunity. We therefore repeated the monocolonization in GF C57Bl/6 mice followed by 8 weeks of topical treatment with IMQ, a TLR7 agonist that has been shown to induce a lupus-like syndrome in mice under specific pathogen-free (SPF) conditions (43,44). After 8 weeks of monocolonization with or without IMQ treatment (until 16 weeks of age), sera and organs were collected from all mice for autoimmune studies (Fig.…”

Predictive value of CD86 for the occurrence of sepsis (Sepsis-3) in patients with infection

“…In the present study, the expression of HLA-DR in patients with sepsis was decreased, consistent with the previous studies, but the expression of CD86 in PBMCs was higher in the sepsis group than in the non-sepsis group, especially in non-surviving patients, which is inconsistent with some previous studies [ 12 , 38 , 39 ]. CD86 can affect the survival and response of T cells through co-stimulation and co-inhibition pathways [ 27 , 40 ]. The T-cell receptor complex recognizes the antigens on the APCs [ 41 ].…”

Identification of driver genes in lupus nephritis based on comprehensive bioinformatics and machine learning

“…Additionally, LN patients’ pDCs produce type I interferons, which can activate B cells and lead to the production of autoreactive antibodies ( 95 – 97 ). Although the presence of other lymphocytes in LN kidney biopsies, such as innate lymphoid cells and γδT cells, has been observed, their exact contribution to the disease remains unclear ( 98 – 102 ). In our study, we observed a significant increase in monocytes and M2 macrophages as the main infiltrating immune cells in the glomeruli of patients with LN.…”