Interactions of surface-expressed TLR-4 and endosomal TLR-9 accelerate lupus progression in anti-dsDNA antibody transgenic mice.

The hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of anti-double-stranded DNA autoantibody (anti-dsDNA) in sera. In addition, pathogen infections coincide frequently with the occurrence of lupus. Our study was designed to investigate the contribution of anti-dsDNA, extracellular and intracellular Toll-like receptors (TLRs), a family of pattern-recognition receptors for sensing invading pathogens, in the pathogenesis of lupus. Although cell surface-expressed TLR4 may promote lupus progression, intracellular nucleic acid-sensing TLR9 plays either stimulatory or protective roles in different murine lupus models. To examine the role of TLR4, TLR9, and anti-dsDNA in SLE, we generated transgenic mice carrying anti-dsDNA antibody transgene and challenged the mice with TLR4- and TLR9-agonists, lipopolysaccharides (LPS), and CpG oligodeoxynucleotide (CpG ODN1826 and 2216), respectively. Splenocytes from these mice were found to secrete higher levels of interleukin-10 (IL-10) and anti-dsDNA when treated with a combination of TLR4 and TLR9 agonists (LPS + CpG). In addition, the transgenic mice were intraperitoneally administered with CpG or combined CpG and LPS to determine whether extracellular TLR4 and intracellular TLR9 activations could affect lupus progression in vivo. It was found that serum levels of anti-dsDNA antibodies and interferon-alpha were higher in CpG + LPS-treated transgenic mice than those in non-transgenic mice. Besides, elevated levels of proteinuria, blood urine nitrogen, and immune complex depositions in kidney were found in treated transgenic mice. Anti-dsDNA and simultaneous activation of surface-expressed TLR4 and endosomal TLR9 are crucial to promote the lupus progression.