Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by autoantibody production and clinical manifestations affecting the skin, joints, kidneys, and central nervous system [1]
Our results showed that Toll-like receptor 7 (TLR7) activation increased the number of patrolling monocytes in the spleen, circulation, and kidneys of NZBWF1 mice
These findings suggest that increased numbers of patrolling monocytes directly drive lupus nephritis
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by autoantibody production and clinical manifestations affecting the skin, joints, kidneys, and central nervous system [1]. Immunosuppressive agents such as antimalarial drugs, hydroxychloroquine (HCQ), non-steroidal anti-inflammatory drugs, glucocorticoids, and mycophenolate mofetil have been administered to control SLE. Causative autoimmune responses are driven by autoreactive B cells that produce autoantibodies to nucleic acid (NA)-associated autoantigens, conventional dendritic cells (cDCs) that produce proinflammatory cytokines, and plasmacytoid dendritic cells (pDCs) that produce type I interferons (IFNs) [2, 3] In addition to these cells, monocytes/macrophages infiltrate glomeruli and play pathogenic roles in glomerular damage associated with SLE, independently of immune complex deposition [4,5,6]
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