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• W2003952183 abstract "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-γ 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. 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-γ 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. The toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) superfamily has a central role for initiating innate antimicrobial immunity and, hence, may contribute to renal pathology in infective pyelonephritis.1.Akira S. Uematsu S. Takeuchi O. Pathogen recognition and innate immunity.Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (8719) Google Scholar,2.Anders H.J. Banas B. Schlondorff D. Signaling danger: toll-like receptors and their potential roles in kidney disease.J Am Soc Nephrol. 2004; 15: 854-867Crossref PubMed Scopus (329) Google Scholar In fact, renal tubular epithelial cells express TLR1-4 and -11 and can produce proinflammatory cytokines and chemokines in response to respective TLR ligands.3.Tsuboi N. Yoshikai Y. Matsuo S. et al.Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells.J Immunol. 2002; 169: 2026-2033Crossref PubMed Scopus (220) Google Scholar, 4.Zhang D.G. Zhang M.S. Hayden M.B. et al.A toll-like receptor that prevents infection by uropathogenic bacteria.Science. 2004; 303: 1522-1526Crossref PubMed Scopus (876) Google Scholar, 5.Hung C.C. Chang C.T. Chen K.H. et al.Upregulation of chemokine CXCL1/KC by leptospiral membrane lipoprotein preparation in renal tubule epithelial cells.Kidney Int. 2006; 69: 1814-1822Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 6.Yang C.W. Hung C.C. Wu M.S. et al.Toll-like receptor 2 mediates early inflammation by leptospiral outer membrane proteins in proximal tubule cells.Kidney Int. 2006; 69: 815-822Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Furthermore, renal dendritic cells contribute to innate immunity in the kidney as they are activated via TLRs either directly by pathogens or by endogenous molecules such as Tamm–Horsfall protein.7.Saemann M.D. Weichhart T. Zeyda M. et al.Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism.J Clin Invest. 2005; 115: 468-475Crossref PubMed Scopus (216) Google Scholar Uropathogenic Escherichia coli (UPEC) is the most common pathogen involved in infective pyelonephritis and UPEC lipopolysaccharide (LPS) ligates TLR4 as part of the LPS receptor complex.8.Poltorak A. He X. Smirnova I. et al.Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.Science. 1998; 282: 2085-2088Crossref PubMed Scopus (6421) Google Scholar We have recently reported experiments with TLR4 bone marrow chimeric mice which showed that TLR4 on intrinsic renal cells as well as on myeloid cells contributes to renal chemokine signaling and subsequent renal abcess formation in infective pyelonephritis with UPEC.9.Patole P.S. Schubert S. Meßmer K. et al.Toll-like receptor-4: intrinsic renal cells and bone marrow-derived cells signal for neutrophil recruitment during infective pyelonephritis.Kidney Int. 2005; 68: 2582-2587Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar What are the molecular mechanisms that control renal TLR signaling? Excessive TLR signaling may lead to severe inflammation and inappropriate immunity-related tissue damage.10.Iwasaki A. Medzhitov R. Toll-like receptor control of the adaptive immune responses.Nat Immunol. 2004; 5: 987-995Crossref PubMed Scopus (3325) Google Scholar In fact, a number of negative regulators of TLRs have been identified, which include splice variants of signaling molecules, soluble TLRs, cleavage enzymes, and receptors of the TLR/IL-1R family, T1/ST2 and toll–IL-1R(TIR)8/SIGIRR.11.Muzio M. Polentarutti N. Bosisio D. et al.Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes.J Leukoc Biol. 2000; 67: 450-456Crossref PubMed Scopus (155) Google Scholar, 12.Liew F.Y. Xu D. Brint E.K. O'Neill L.A. Negative regulation of toll-like receptor-mediated immune responses.Nat Rev Immunol. 2005; 5: 446-458Crossref PubMed Scopus (1255) Google Scholar, 13.Wells C.A. Chalk A.M. Forrest A. et al.Alternate transcription of the Toll-like receptor signaling cascade.Genome Biol. 2006; 7: R10Crossref PubMed Scopus (73) Google Scholar The Tir8/Sigirr gene was identified by searching EST databases for TIR domain-containing sequences of yet unknown members of the TLR/IL-1R family.14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar,15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar TIR8/SIGIRR is the only TIR domain-containing member of the TLR/IL-1R superfamily that has a single extracellular immunoglobulin (Ig) domain.14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar,15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar The intracellular domain of TIR8/SIGIRR differs from the typical C terminus of TLR/IL-1Rs and is similar to that of the Drosophila toll protein.14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar Neither IL-1 nor other ligands bind to TIR8/SIGIRR. TIR8/SIGIRR does not activate nuclear factor-κB (NF-κB),14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar,16.Norris J.L. Manley J.L. Functional interactions between the pelle kinase, Toll receptor, and tube suggest a mechanism for activation of dorsal.Genes Dev. 1996; 10: 862-872Crossref PubMed Scopus (37) Google Scholar most probably because it does not retain two amino acids (Ser447 and Tyr536) in the highly conserved TIR domain.14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar TIR8/SIGIRR was proposed as an endogenous inhibitor of TLR signaling, because overexpression of TIR8/SIGIRR in Jurkat or HepG2 cells substantially reduced IL-1- or IL-18-induced activation of NF-κB.15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar, 17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar, 18.Qin J. Qian Y. Yao J. et al.SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms.J Biol Chem. 2005; 280: 25233-25241Crossref PubMed Scopus (181) Google ScholarTir8/Sigirr-deficient mice are more susceptible to dextran-induced inflammatory bowel disease and a TIR8/Sigirr-blocking antibody was shown to aggravate Pseudomonas aeruginosa keratitis in Balb/c mice.19.Garlanda C. Riva F. Polentarutti N. et al.Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family.Proc Natl Acad Sci USA. 2004; 101: 3522-3526Crossref PubMed Scopus (231) Google Scholar,20.Huang X. Hazlett L.D. Du W. Barrett R.P. SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling.J Immunol. 2006; 177: 548-556Crossref PubMed Scopus (74) Google Scholar This was referred to TIR8/Sigirr-mediated suppression of TLR signaling in dendritic cells, which express TIR8/Sigirr constitutively. Interestingly, TIR8/Sigirr mRNA is expressed at high levels in the murine and human kidney in comparison to other solid organs including lymphoid tissues.15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar,17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar This may either relate to TIR8/Sigirr expression in intrarenal myeloid cells or tubular cells. We hypothesized a role for TIR8/Sigirr in regulating TLR signaling in both cell types during exposure to UPEC LPS. However, we discovered that renal TLR signaling is independent of TIR8/Sigirr expression in renal tubular epithelial cells. Obviously, the regulation and function of TIR8/Sigirr is different in immune and nonimmune cells in the kidney. TLR function has been reported to be age-dependent;21.Renshaw M. Rockwell J. Engleman C. et al.Cutting edge: impaired Toll-like receptor expression and function in aging.J Immunol. 2002; 169: 4697-4701Crossref PubMed Scopus (509) Google Scholar hence, we analyzed TIR8/Sigirr mRNA levels by real-time reverse transcription (RT)–PCR in C57BL/6 mice, either 10 days, 6 weeks, or 1 year of age. At 6 weeks of age, high levels of TIR8/Sigirr mRNA were found in kidneys, threefold compared to respective TIR8/Sigirr levels in spleen (Figure 1a). By contrast, brain, heart, lung, liver, small intestine, colon, skin, and muscle expressed TIR8/Sigirr mRNA at lower levels as in spleen. In most organs, TIR8/Sigirr mRNA levels declined from young to old age. Interestingly, TIR8/Sigirr mRNA levels in 6-week-old C57BL/6 mice were seven- to eightfold higher as compared to 10-day- or 1-year-old mice. The prominent expression of TIR8/Sigirr in kidneys of 6-week-old mice was confirmed on the protein level by Western blot (Figure 1b). Cortex and medulla from kidneys of 6-week-old C57BL/6 mice expressed equal levels of TIR8/Sigirr mRNA, suggesting a tubular or interstitial origin rather than glomerular cells, which predominantely locate to the renal cortex (data not shown). In fact, unlike primary mesangial cells tubular epithelial cells and resident CD11b/F4/80-positive renal myeloid cells both expressed TIR8/Sigirr mRNA (Figure 1c). The latter cells localize to the interstitium of the renal cortex and medulla of mice (Figure 1d). These data indicate that the profound renal TIR8/Sigirr expression originates from tubular epithelial cells and intrarenal immune cells, resident antigen-presenting cells. The transmembrane molecule TIR8/Sigirr has been reported to suppress LPS signaling in Jurkat cells by interacting with the intracellular domain of TLR4 and both extracellular Ig domain and the intracellular TIR domain of IL-1R.18.Qin J. Qian Y. Yao J. et al.SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms.J Biol Chem. 2005; 280: 25233-25241Crossref PubMed Scopus (181) Google Scholar Thus, TIR8/Sigirr should localize to outer membranes of these cells. In fact, flow cytometry of primary tubular epithelial cells using a TIR8/Sigirr-specific antibody revealed a robust signal on the cell surface (Figure 2a). The cellular distribution of TIR8/Sigirr was confirmed by the immunostaining on primary tubular epithelial cells. Positive staining signals were detected at outer membranes only (Figure 2c). The specificity of positive signals in both methods was demonstrated by using tubular epithelial cells prepared from Tir8/Sigirr-deficient mice (Figure 2b and d). TIR8/Sigirr immunostaining on kidney sections prepared from 6-week-old C57BL/6 mice revealed positive staining signals at basolateral and luminal membranes of tubular epithelial cells (Figure 2e). In proximal tubular epithelial cells, the colocalization with the luminal brush border (costainined with fluorescein isothiocyanate–phalloidin) was apparent (Figure 2e). Glomeruli stained negative for TIR8/Sigirr (not shown). Negative controls included staining of renal sections from Tir8/Sigirr-deficient mice (Figure 2f), omitting the primary antibody (not shown) or preabsorbing the primary antibody with TIR8/Sigirr-overexpressing human embryonic kidney 293 cells (not shown). Thus, TIR8/Sigirr is expressed on basolateral and luminal membranes of tubular epithelial cells in the mouse kidney. We have previously shown that both resident intrarenal myloid cells and tubular epithelial cells contribute to renal TLR4 signaling in infective pyelonephritis with uropathogenic Escherichia coli (UPEC).9.Patole P.S. Schubert S. Meßmer K. et al.Toll-like receptor-4: intrinsic renal cells and bone marrow-derived cells signal for neutrophil recruitment during infective pyelonephritis.Kidney Int. 2005; 68: 2582-2587Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Hence, we hypothesized that lack of TIR8/Sigirr would enhance LPS-induced renal chemokine release as a result of uncoupling TLR4 signaling in both cell types. In fact, kidney slices from Tir8/Sigirr-deficient mice produced much more Ccl2 and Cxcl2 on exposure to 1 μg/ml UPEC LPS for 24 h (Figure 3a). However, when we exposed primary tubular epithelial cells or CD11b-positive renal myeloid cells to LPS, lack of TIR8/Sigirr was found to enhance LPS-induced Ccl2 or CxCL2 production only in the myeloid cells but not in the tubular epithelial cells (Figure 3b and c). These data suggest that the suppressive effect of TIR8/Sigirr on renal TLR4 signaling relates to TIR8/Sigirr in intrarenal myeloid cells and is independent of TIR8/Sigirr in tubular epithelial cells. LPS-induced chemokine expression is mediated through NF-κB. Because transfection of primary monocytes and tubular cells with a NF-κB-reporter gene construct was limited by low cell survival we used a p50 (NLS) antibody to determine nuclear translocation of NF-κB as a marker of NF-κB activation. CD11b-positive monocytes and tubular epithelial cells were stained after 1 h of stimulation with either medium or LPS. The data obtained were consistent with those obtained from LPS-induced Ccl2 and Cxcl2 production (Figure 4a), indicating that LPS-induced TLR signaling is independent of TIR8/Sigirr in tubular epithelial cells. Next, we tested whether TIR8/Sigirr affects signaling of TLRs other than TLR4 in tubular epithelial cells. Spleen monocytes were used as a positive control for TIR8/Sigirr function. Primary tubular epithelial cells and spleen monocytes were isolated either from 6-week-old wild-type or Tir8/Sigirr-deficient mice. As with the TLR4 ligand LPS, Tir8/Sigirr-deficient monocytes produced increased amounts of Ccl2 when exposed to ligands for TLR1/2 (Pam3Cys), TLR3 (poly I:C RNA), and TLR9 (CpG-DNA) (Figure 4b). In tubular epithelial cells, lack of TIR8/Sigirr had no such effect and no response to CpG-DNA was observed, because tubular epithelial cells do not express TLR9 (Figure 4c). These data show that TIR8/Sigirr does not affect signaling through TLR tubular epithelial cells. Do the cell type-specific effects of TIR8/Sigirr on TLR signaling relate to a modulatory effect on TLR expression levels? To answer this question, TLR1-9 and -11 mRNA expression levels were determined by real-time RT–PCR from monocytes and tubular epithelial cells kept under normal culture conditions. Monocytes expressed all TLRs and lack of TIR8/Sigirr increased mRNA levels of TLR1 (13-fold), TLR5 (23-fold), TLR6 (sevenfold), TLR7 (eightfold), TLR9 (12-fold), and TLR11 (23-fold) as compared to monocytes isolated from wild-type mice (Figure 5a). Lack of TIR8/Sigirr did not affect mRNA expression of TLR2, -3, -4, and -8 in monocytes. By contrast, tubular epithelial cells expressed TLR1-4 and -11 mRNA independent of TIR8/Sigirr (Figure 5b). Apparently, TIR8/Sigirr is a suppressor of TLR1, -5, - 6, -7, -9, and -11 mRNA expression in monocytes, but has no effect on the respective TLRs coexpressed by tubular epithelial cells, that is TLR1 and TLR11. Next, we examined whether LPS or interferon-γ (IFN-γ)/tumor necrosis factor (TNF) stimulation suppress TIR8/Sigirr mRNA levels in monocytes and tubular epithelial cells. In fact, both LPS and IFN-γ/TNF reduced TIR8/Sigirr mRNA levels in tubular epithelial cells (Figure 6a and b). By contrast, LPS and IFN-γ/TNF both increased TIR8/Sigirr expression in monocytes in a dose-dependent manner with highest mRNA levels after 18 h (Figure 6). Together, these data suggest that constitutive TLR4 signaling consistently suppresses TIR8/Sigirr mRNA in tubular epithelial cells and monocytes. By contrast, LPS or cytokine exposure rather upregulates TIR8/Sigirr in monocytes but not in tubular epithelial cells, indicating cell type-specific regulation of TIR8/Sigirr. Can the different functional role of TIR8/Sigirr in monocytes and tubular epithelial cells be explained by either the expression of different splice variants or by different post-translational modifications? We performed real-time RT–PCR using primers specific for the intracellular and extracellular domain of TIR8/Sigirr (Figure 7a). Monocytes and tubular epithelial cells expressed comparable levels of both the intracellular and extracellular domain of TIR8/Sigirr (Figure 7b). This was confirmed by Northern blot analysis. Total RNA was extracted from kidneys and spleens from wild-type and Tir8/Sigirr-deficient mice. The RNA was hybridized with a P32-labeled full-length probe (data not shown) or a shorter probe matching the extracellular part of TIR8/Sigirr. A single TIR8/Sigirr mRNA transcript of 3.5 kB was detected in both kidney and spleen and no further splice variants were detected (Figure 7c). However, cell type-specific functions of proteins may relate to post-translational modifications. In fact, Western blot of total kidney protein isolates revealed two TIR8/Sigirr-specific bands of 75 and 90 kDa (Figure 7d). Next, we prepared renal cell suspensions and isolated CD11b-positive myeloid cells and CD11b-negative renal cells of nonmyeloid origin. The renal myeloid cells expressed the larger 90 kDa form of TIR8/Sigirr, whereas the nonmyeloid renal cells predominantely expressed the smaller form of 75 kDa (Figure 7e). Protein size depends on protein glycosylation. TIR8/Sigirr carries five putative glycosylation sites and the predicted and actual molecular weight of TIR8/Sigirr suggest extensive glycosylation.14.Thomassen E. Renshaw B.R. Sims J.E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily.Cytokine. 1999; 11: 389-399Crossref PubMed Scopus (165) Google Scholar We tested the glycosylation of TIR8/Sigirr in the two types of renal cells by digesting protein isolates from renal myeloid and nonmyeloid cells with peptide-N-glycosidase F (PNGaseF). This glycosidase digests N-linked but not N-glycans with fucose-linked α1,3 to the Asn-bound N-acetylglucosamine, O-linked oligosaccharides or glycosylphosphatidylinositol lipid anchors from glycoproteins, and hence, allows the detection of glycosylation variants. PNGaseF treatment reduced the molecular mass of TIR8/Sigirr in both CD11b-positive and -negative renal cells (Figure 7e). CD11b-positive and -negative renal cells both carry TIR8/Sigirr glycosylated at identical sites, digested by PNGaseF to a 60-kDa protein. The CD11b-negative (nonimmune) renal cells, however, contained additional TIR8/Sigirr glycosylation variants that are digested by PNGaseF to two other variants with a size of approximately 45 and 50 kDa. Furthermore, we used benzyl-N-acetylgalactosamine (benzyl-GalNAc, an inhibitor of O-glycosylation, to investigate the O-glycosylation of TIR8/Sigirr in renal immune and nonimmune cells. Benzyl-GalNAc treatment did not change the size of the larger glycoform of TIR8/Sigirr in renal myeloid and nonmyeloid cells (Figure 7f), hence, the larger TIR8/Sigirr glycoform is not O-glycosilated. By contrast, exposing renal nonimmune cells to benzyl-GalNAc reduced the size of the smaller predominant TIR8/Sigirr glycoform to about 60 kDa, suggestive of O-glycosylation of this protein (Figure 7f). These data show that the cell type-specific functions of TIR8/Sigirr in the kidney do not relate to different splicing but are associated with different glycosylation variants. This study was motivated by two observations: First, our previous observation that TLR4 on intrinsic renal cells as well as bone marrow-derived cells contributes to innate immunity in infective pyelonephritis9.Patole P.S. Schubert S. Meßmer K. et al.Toll-like receptor-4: intrinsic renal cells and bone marrow-derived cells signal for neutrophil recruitment during infective pyelonephritis.Kidney Int. 2005; 68: 2582-2587Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar and second, TIR8/Sigirr, a negative regulator of TLR/IL-1R signaling was reported to be expressed at high levels in the kidney.15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar,17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar We hypothesized that TIR8/Sigirr would control inappropriate TLR signaling in the kidney and, if so, that TIR8/Sigirr on renal myeloid and nonimmune intrinsic renal cells would contribute to this phenomenon. Although we confirmed the first part of our hypothesis, our data do not support the latter. Our data clearly demonstrate that TIR8/Sigirr suppresses renal Ccl2 production on exposure to LPS. This is consistent with the exacerbation of various other inflammatory disease models that have been induced in Tir8/Sigirr-deficient mice, for example endotoxic shock,17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar dextran-induced colitis,19.Garlanda C. Riva F. Polentarutti N. et al.Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family.Proc Natl Acad Sci USA. 2004; 101: 3522-3526Crossref PubMed Scopus (231) Google Scholar and Pseusomonas aeruginosa keratitis.20.Huang X. Hazlett L.D. Du W. Barrett R.P. SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling.J Immunol. 2006; 177: 548-556Crossref PubMed Scopus (74) Google Scholar Recognition of LPS in the kidney may involve various cell types which can broadly be classified into renal immune cells and nonimmune cells. Intrarenal immune cells are mainly resident antigen-presenting cells which originate from the bone marrow and form a dense network in the interstitial space that grid the tubular compartment in the healthy kidney.22.Kruger T. Benke D. Eitner F. et al.Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis.J Am Soc Nephrol. 2004; 15: 613-621Crossref PubMed Scopus (212) Google Scholar,23.Soos T.J. Sims T.N. Barisoni L. et al.CX(3)CR1(+) interstitial dendritic cells form a contiguous network throughout the entire kidney.Kidney Int. 2006; 70: 591-596Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar Consistent with the previous description of TIR8/Sigirr's function in dendritic cells and monocytes,15.Polentarutti N. Rol G.P. Muzio M. et al.Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR.Eur Cytokine Netw. 2003; 14: 211-218PubMed Google Scholar,17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar we found that TIR8/Sigirr suppresses LPS-induced Ccl2 and Cxcl2 production in renal antigen-presenting cells. Wald et al.17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar reported a similar role for TIR8/Sigirr in renal tubular cells but in their study kidney cell suspensions were prepared from Tir8/Sigirr-deficient mice in a mixed genetic background. In this study, we applied more stringent preparation techniques for primary tubular cells, as we found that kidney cell suspensions prepared following the protocol reported by Wald et al.17.Wald D. Qin J. Zhao Z. et al.SIGIRR, a negative regulator of Toll-like receptor–interleukin 1 receptor signaling.Nat Immunol. 2003; 4: 920-927Crossref PubMed Scopus (505) Google Scholar are commonly contaminated by myeloid cells, compromising conclusions on the role of TIR8/Sigirr in tubular epithelial cells. By using the protocol reported by Tsuboi et al.3.Tsuboi N. Yoshikai Y. Matsuo S. et al.Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells.J Immunol. 2002; 169: 2026-2033Crossref PubMed Scopus (220) Google Scholar the primary tubular epithelial cell population was >95%. Furthermore, we have now backcrossed Tir8/Sigirr mutants for six generations to the C57BL/6 background to prepare monocytes and tubular epithelial cells from mice with a predicted >95% identical background as compared to wild-type controls.24.Mutant mice and neuroscience: recommendations concerning genetic background. Banbury conference on genetic background in mice.Neuron. 1997; 19: 755-759Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar,25.Sigmund C.D. Viewpoint: are studies in genetically altered mice out of control?.Arterioscler Thromb Vasc Biol. 2000; 20: 1425-1429Crossref PubMed Scopus (105) Google Scholar In fact, by using a pure tubular epithelial cell population no impact of TIR8/Sigirr on TLR signaling could be detected. Obviously, intrarenal antigen-presenting cells and tubular epithelial cells contribute to renal TLR4 signaling. Although TIR8/Sigirr is expressed by both cell types, TIR8/Sigirr suppresses TLR signaling only in intrarenal antigen-presenting cells and not in tubular epithelial cells. Although reducing TLR signaling in renal antigen-presenting cells may avoid inappropriate immunity-related tissue injury, an unrestricted activation of tubular cells may support the induction of necessary epithelial stress response elements to cope with microbial infection. Intrigued by the lack of suppressive function of TIR8/Sigirr in tubular epithelial cells, we first excluded alternativ" @default.
• W2003952183 created "2016-06-24" @default.
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• W2003952183 creator A5037512675 @default.
• W2003952183 creator A5040551472 @default.
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• W2003952183 date "2007-07-01" @default.
• W2003952183 modified "2023-10-18" @default.
• W2003952183 title "Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells" @default.
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