Toll‐like Receptor 2 Is Required for Autoantibody Production and Development of Renal Disease in Pristane‐Induced Lupus

Abstract

Objective. The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus.Methods. Lupus-like disease in C57BL/6 and TLR-2 ؊/؊ mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay.Results. Pristane-injected TLR-2 ؊/؊ mice generated reduced numbers of splenic CD138؉/cytoplasmic L/L chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wildtype controls. TLR-2 deficiency prevented the pristaneinduced systemic release of interleukin-6 (IL-6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c؉ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2 ؊/؊ mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells.Conclusion. TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE.

Endogenous interleukin (IL)-17A promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane

“…Both TLR-2 [43] and TLR-4 [15] are pathogenic in this model. When WT splenocytes were cultured with a TLR-2 ligand there was a significant increase in IL-17A production, concordant with our findings in experimental vasculitis, where TLR-2 ligation promoted IL-17A responses and subsequent renal injury [22].…”

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

“…Using these Ncf1** mice we tested the influence of NOX2-derived ROS in a mouse model of lupus induced by intraperitoneal injection of the alkane oil pristane. Current concepts envisage that autoreactivity in PIL follows massive cell infiltration accompanied by cell death in the peritoneum after pristane injection and causing an overload of the clearance machinery (51). We aimed to shed light on the role of ROS and especially NETs in the etiopathogenesis of murine lupus by examining PIL in Ncf1** mice.…”

Repairing Effects of Aqueous Extract of Kalanchoe pinnata (Lmk) Pers. on Lupus Nephritis Mice

“…Proteinuria is a parameter for severity of nephritis. 22,23 (-/-Moreover, there was no severe proteinuria obtained on the mice until the 6 th month after the induction. The mice only had mild proteinuria + (30 mg/dL) which revealed the low disease progress.…”