Abstract

Mounting evidence indicates the importance of aberrant Toll-like receptor 7 (TLR7) signaling in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of disease progression remains unclear. An imiquimod (IMQ)-induced lupus model was used to analyze the lupus mechanism related to the aberrant TLR7 signals. C57BL/6 mice and NZB/NZW mice were treated with topical IMQ, and peripheral blood, draining lymph nodes, and kidneys were analyzed focusing on monocytes and monocyte-related cells. Monocytes expressed intermediate to high levels of TLR7, and the long-term application of IMQ increased Ly6Clo monocytes in the peripheral blood and Ly6Clo monocyte-like cells in the lymph nodes and kidneys, whereas Ly6Chi monocyte-like cell numbers were increased in lymph nodes. Ly6Clo monocyte-like cells in the kidneys of IMQ-induced lupus mice were supplied by bone marrow-derived cells as demonstrated using a bone marrow chimera. Ly6Clo monocytes obtained from IMQ-induced lupus mice had upregulated adhesion molecule-related genes, and after adoptive transfer, they showed greater infiltration into the kidneys compared with controls. RNA-seq and post hoc PCR analyses revealed Ly6Clo monocyte-like cells in the kidneys of IMQ-induced lupus mice had upregulated macrophage-related genes compared with peripheral blood Ly6Clo monocytes and downregulated genes compared with kidney macrophages (MF). Ly6Clo monocyte-like cells in the kidneys upregulated Il6 and chemoattracting genes including Ccl5 and Cxcl13. The higher expression of Il6 in Ly6Clo monocyte-like cells compared with MF suggested these cells were more inflammatory than MF. However, MF in IMQ-induced lupus mice were characterized by their high expression of Cxcl13. Genes of proinflammatory cytokines in Ly6Chi and Ly6Clo monocytes were upregulated by stimulation with IMQ but only Ly6Chi monocytes upregulated IFN-α genes upon stimulation with 2′3′-cyclic-GMP-AMP, an agonist of stimulator of interferon genes. Ly6Chi and Ly6Clo monocytes in IMQ-induced lupus mice had different features. Ly6Chi monocytes responded in the lymph nodes of locally stimulated sites and had a higher expression of IFN-α upon stimulation, whereas Ly6Clo monocytes were induced slowly and tended to infiltrate into the kidneys. Infiltrated monocytes in the kidneys likely followed a trajectory through inflammatory monocyte-like cells to MF, which were then involved in the development of nephritis.

Highlights

  • Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of many types of autoantibodies, especially anti-nuclear antibodies [1]

  • Peripheral blood CD11b+ cells among lineage marker (Lin: CD3, CD19, Ly6G, NK1.1) negative cells were mostly composed of monocytes that expressed CD115 and CX3CR1 (Supplementary Figures 1A, B)

  • Considering the importance of Toll-like receptor 7 (TLR7) signals in monocytes and monocyte-related cells in the pathogenesis of SLE [11, 18], we focused on the expression of TLR7 in relation to monocytes

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Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of many types of autoantibodies, especially anti-nuclear antibodies [1]. Despite the postulated central role of B cells and autoantibodies in SLE, many interventions that target this compartment have not succeeded [2]. Among the innate immune signaling molecules, polymorphisms of Toll-like receptor 7 (TLR7) were reported to have a significant association with the development of SLE [6], and the epicutaneous application of TLR7 induced lupus-like disease in mice [7]. PDC have critical roles in the pathogenesis of SLE through the production of IFNa following TLR7 activation [8]. A potential relationship between TLR7 stimulation and lupus-like disease development in the imiquimod (IMQ)-induced lupus model is unclear, other than the mechanism involving pDC

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