Background. How microbial infections exacerbate immune complex glomerulonephritis remains speculative. Toll-like receptors (TLRs) may be involved in this phenomenon, because TLRs have potent immunostimulatory functions when exposed to selected pathogen-associated molecules.

Methods. We addressed this issue by characterizing the expression of TLR1–9 in MRL^lpr/lpr mice that spontaneously develop immune complex glomerulonephritis as part of a systemic lupus-like autoimmune syndrome.

Results. Five-week-old healthy MRL^lpr/lpr mice expressed TLR3 mRNA in kidneys at comparable levels as in the spleen, while all other TLRs were expressed at low levels in the kidney. In 20-week-old nephritic MRL^lpr/lpr mice, renal mRNA levels had increased for TLR1–9. Renal TLR mRNA originated at least in part from glomeruli as evidenced by real-time RT-PCR from laser capture microdissected glomeruli. Immunostaining for TLR3, TLR7 and TLR9 revealed their expression by F4/80-positive infiltrating macrophages in 20-week-old nephritic MRL^lpr/lpr mice. In addition, TLR3 localized to glomerular mesangial cells. Cultured mesangial cells expressed TLR1–4 and TLR6, while murine macrophages expressed TLR1–9. TNF-α and IFN-γ induced TLR2, TLR3 and TLR6 mRNA in mesangial cells, while they down-regulated TLR1–9 mRNA in macrophages. Stimulation of both cell types with ligands for TLR1–4, TLR5, TLR7 and TLR9 induced IL-6 production consistent with their respective TLR expression patterns. TNF-α and IFN-γ enhanced ligand-induced IL-6 production in both cell types irrespective of their modulatory effect on respective TLR mRNA levels.

Conclusion. Thus, cell-type-specific expression and regulation of TLRs may be involved in infection-associated exacerbation of immune complex glomerulonephritis of MRL^lpr/lpr mice.