Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction.

Innate immune activation via IL-1R or Toll-like receptors (TLR)
contibutes to acute kidney injury but its role in tissue remodeling
during chronic kidney disease is unclear. SIGIRR is an inhibitor of
TLR-induced cytokine and chemokine expression in intrarenal immune
cells, therefore, we hypothesized that Sigirr-deficiency would
aggravate postobstructive renal fibrosis. The expression of TLRs as
well as endogenous TLR agonists increased within six days after UUO
in obstructed compared to unobstructed kidneys while SIGIRR itself
was downregulated by day 10. However, lack of SIGIRR did not affect
the intrarenal mRNA expression of proinflammatory and profibrotic
mediators as well as the numbers of intrarenal macrophages and T
cells or morphometric markers of tubular atrophy and interstitial
fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at
the level of the intracellular adaptor molecule MyD88 UUO
experiments were also performed in mice deficient for either MyD88,
TLR2 or TLR9. After UUO there was no significant change of tubular
interstitial damage and interstitial fibrosis in neither of these
mice compared to wildtype counterparts. Additional in-vitro studies
with CD90+ renal fibroblasts revealed that TLR agonists induce the
expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or
smooth muscle actin. Together, postobstructive renal interstitial
fibrosis and tubular atrophy develop independent of SIGIRR, TLR2,
TLR9, and MyD88. These data argue against a significant role of
these molecules in renal fibrosis.