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


CONCLUSIONS
Thus, cell-type-specific expression and regulation of TLRs may be involved in infection-associated exacerbation of immune complex glomerulonephritis of MRLlpr/lpr mice.
Patole
Prashant S
PS
Nephrological Center, Medizinische Poliklinik, Universität München, Pettenkoferstr. 8a 80336 München, Germany.
Pawar
Rahul D
RD
Lech
Maciej
M
Zecher
Daniel
D
Schmidt
Holger
H
Segerer
Stephan
S
Ellwart
Andreas
A
Henger
Anna
A
Kretzler
Matthias
M
Anders
Hans-Joachim
HJ
D000818:Animals; D002460:Cell Line; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D051193:Toll-Like Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D051193:Toll-Like Receptors