Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells.
Toll-like receptors (TLRs) exist on both myeloid and intrinsic renal cells contributing to the initiation of innate immunity during renal infection with uropathogenic Escherichia coli. Toll-interleukin 1 receptor (IL-1R) (TIR)8/SIGIRR is an orphan receptor of the TLR/IL-1R family, which suppresses TLR signaling of immune cells and is highly expressed in the kidney. Lack of TIR8/SIGIRR is associated with enhanced renal chemokine signaling upon exposure to lipopolysaccharide (LPS). This was because of TIR8/SIGIRR expression on resident intrarenal myeloid cells rather than tubular epithelial cells which express it on basolateral and luminal membranes. The lack of TIR8/SIGIRR does not enhance TLR/IL-1R signaling in tubular epithelial cells as was observed in monocytes. TIR8/SIGIRR is induced in monocytes treated with LPS or tumor necrosis factor and interferon-gamma in a dose-dependent manner but was downregulated in treated tubule epithelial cells. This cell type-specific regulation and function did not relate to mRNA splice variants but was associated with N- and O-glycosylation of the receptor in renal cells of myeloid and nonmyeloid origin. Our studies show that resident myeloid cells contribute to TLR-mediated antimicrobial immunity in the kidney and that this function is controlled by Tir8/sigirr. TIR8/SIGIRR does not suppress TLR signaling in tubular epithelial cells, which supports their role as sensors of microbial infection in the kidney.
Lech
M
M
Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany.
Garlanda
C
C
Mantovani
A
A
Kirschning
C J
CJ
Schlöndorff
D
D
Anders
H-J
HJ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate; D007668:Kidney / Q000166:cytology* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes; D022423:Myeloid Cells; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C484529:SIGIRR protein, mouse