Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice.

Abstract

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 MRLlpr/lpr mice that spontaneously develop immune complex glomerulonephritis as part of a systemic lupus-like autoimmune syndrome.

RESULTS:

Five-week-old healthy MRLlpr/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 MRLlpr/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 MRLlpr/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-alpha and IFN-gamma 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-alpha and IFN-gamma 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 MRLlpr/lpr mice.

• Authors: Prashant S Patole, Rahul D Pawar, Maciej Lech, Daniel Zecher, Holger Schmidt, Stephan Segerer, Andreas Ellwart, Anna Henger, Matthias Kretzler, Hans-Joachim Anders
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 21 Issue 11 Pg. 3062-73 (Nov 2006) ISSN: 0931-0509 [Print] England
• PMID: 16954173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Toll-Like Receptors

Topics

• Animals
• Cell Line
• Immune Complex Diseases (immunology, metabolism, pathology)
• Lupus Nephritis (immunology, metabolism, pathology)
• Mice
• Mice, Inbred MRL lpr
• Organ Specificity (genetics, immunology)
• RNA, Messenger (biosynthesis)
• Toll-Like Receptors (biosynthesis, genetics, metabolism)