The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney
Abstract
Th1 and Th17 cells, T helper (Th) subtypes, are key inducers of renal fibrosis. The molecular mechanisms of their recruitment into the kidney, however, are not well understood. Here, we show that biglycan, a proteoglycan of the extracellular matrix, acting in its soluble form as a danger signal, stimulates autonomously the production of Th1 and Th17 chemoattractants CXCL10 and CCL20 in macrophages. In the presence of IFNγ, biglycan synergistically stimulates CXCL9. In macrophages deficient for TLR2, TLR4, and their adaptor molecules MyD88 or TRIF, we identified highly selective mechanisms of biglycan-dependent Th1/17 chemoattraction. Thus, the expression of CXCL9 and CXCL10, common chemoattractants for CXCR3-positive Th1 and Th17 cells, is triggered in a biglycan-TLR4/TRIF-dependent manner. By contrast, biglycan induces CCL20 chemokine production, responsible for CCR6-positive Th17 cell recruitment, in a TLR2/4/MyD88-dependent manner. Importantly, at the onset of diabetes mellitus and lupus nephritis we provide evidence for biglycan-dependent recruitment of Th1 and Th17 cells, IFNγ and IL-17 production, and development of albuminuria in mice lacking or overexpressing soluble biglycan. Furthermore, by genetic ablation of Cxcl10 we showed in vivo involvement of this chemokine in biglycan-dependent recruitment of Th1 and Th17 cells into the kidney. Finally, a positive correlation of biglycan and CXCL10/CXCL9 levels was detected in plasma from patients with diabetic nephropathy a…
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Notably, CXCL10 can recruit lymphocytes, including Th1 and Th17 cells, to inflammatory sites, thereby amplifying local immune responses46,47.”
From Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis (2026) · cites this paper as [47]
Citations
Cites
LPS/TLR4 signal transduction pathway
Lu, Y.-C., Yeh, W.-C., & Ohashi, P. S. (2008) · Cytokine · doi:10.1016/j.cyto.2008.01.006 · Cited by 3,301
Late Developmental Plasticity in the T Helper 17 Lineage
Lee, Y. K., Turner, H., Maynard, C. L., Oliver, J. R., Chen, D., Elson, C. O., & Weaver, C. T. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.005 · Cited by 1,053
Schaefer, L., Babelova, A., Kiss, E., Hausser, H.-J., Baliova, M., Krzyzankova, M., Marsche, G., Young, M. F., Mihalik, D., Götte, M., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23755 · Cited by 850
Self-citationMoreth, K., Brodbeck, R., Babelova, A., Gretz, N., Spieker, T., Zeng-Brouwers, J., Pfeilschifter, J., Young, M. F., Schaefer, R. M., & Schaefer, L. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42213 · Cited by 207
Self-citation
Flagged first, then by citations
Research works printed but not linked: 78
- Hill, 2016, Global prevalence of chronic kidney disease - a systematic review and meta-analysis, PLoS One, 11, 10.1371/journal.pone.0158765 · DOI
- Anand, 2017, Do attributes of persons with chronic kidney disease differ in low-income and middle-income countries compared with high-income countries? Evidence from population-based data in six countries, BMJ Glob. Health, 2, 10.1136/bmjgh-2017-000453 · DOI
- Stanifer, 2016, Chronic kidney disease in low- and middle-income countries, Nephrol. Dial. Transplant., 31, 868, 10.1093/ndt/gfv466 · DOI
- Kiuchi, 2016, Chronic kidney disease and risk factors responsible for sudden cardiac death: a whiff of hope?, Kidney Res. Clin. Pract., 35, 3, 10.1016/j.krcp.2015.11.003 · DOI
- Klinkhammer, 2017, Treatment of renal fibrosis-turning challenges into opportunities, Adv. Chronic Kidney Dis., 24, 117, 10.1053/j.ackd.2016.11.002 · DOI
- Dolman, 2010, Drug targeting to the kidney: advances in the active targeting of therapeutics to proximal tubular cells, Adv. Drug Deliv. Rev., 62, 1344, 10.1016/j.addr.2010.07.011 · DOI
- Breyer, 2016, The next generation of therapeutics for chronic kidney disease, Nat. Rev. Drug Discov., 15, 568, 10.1038/nrd.2016.67 · DOI
- MacKinnon, 2006, Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data, Am. J. Kidney Dis., 48, 8, 10.1053/j.ajkd.2006.04.077 · DOI
- Zhang, 2017, Effects of RAAS inhibitors in patients with kidney disease, Curr. Hypertens. Rep., 19, 72, 10.1007/s11906-017-0771-9 · DOI
- Zheng, 2016, Immune cells and inflammation in diabetic nephropathy, J. Diab. Res., 2016, 1841690
- Donate-Correa, 2015, Inflammatory cytokines in diabetic nephropathy, J. Diab. Res., 2015, 948417
- Segerer, 2008, B cells and tertiary lymphoid organs in renal inflammation, Kidney Int., 73, 533, 10.1038/sj.ki.5002734 · DOI
- Kulkarni, 2008, Chemokines in lupus nephritis, Front. Biosci., 13, 3312, 10.2741/2927 · DOI
- Bradshaw, 2009, Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells, J. Immunol., 183, 4432, 10.4049/jimmunol.0900576 · DOI
- Kim, 2015, Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression, Transl. Res., 166, 375, 10.1016/j.trsl.2015.04.013 · DOI
- Moon, 2012, Aberrant recruitment and activation of T cells in diabetic nephropathy, Am. J. Nephrol., 35, 164, 10.1159/000334928 · DOI
- Bagavant, 2009, Pathogenesis of kidney disease in systemic lupus erythematosus, Curr. Opin. Rheumatol., 21, 489, 10.1097/BOR.0b013e32832efff1 · DOI
- Steinmetz, 2009, CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis, J. Immunol., 183, 4693, 10.4049/jimmunol.0802626 · DOI
- Imani, 1993, Advanced glycosylation end product-specific receptors on human and rat T-lymphocytes mediate synthesis of interferon gamma: role in tissue remodeling, J. Exp. Med., 178, 2165, 10.1084/jem.178.6.2165 · DOI
- Krebs, 2016, CD4+ T cell fate in glomerulonephritis: a tale of Th1, Th17, and novel Treg subtypes, Mediat. Inflamm., 2016, 5393894, 10.1155/2016/5393894 · DOI
- Krebs, 2017, T helper type 17 cells in immune-mediated glomerular disease, Nat. Rev. Nephrol., 13, 647, 10.1038/nrneph.2017.112 · DOI
- Kurts, 2013, The immune system and kidney disease: basic concepts and clinical implications, Nat. Rev. Immunol., 13, 738, 10.1038/nri3523 · DOI
- Bromley, 2008, Orchestrating the orchestrators: chemokines in control of T cell traffic, Nat. Immunol., 9, 970, 10.1038/ni.f.213 · DOI
- Groom, 2011, CXCR3 in T cell function, Exp. Cell Res., 317, 620, 10.1016/j.yexcr.2010.12.017 · DOI
- Krebs, 2016, Autoimmune renal disease is exacerbated by S1P-Receptor-1-dependent intestinal Th17 cell migration to the kidney, Immunity, 45, 1078, 10.1016/j.immuni.2016.10.020 · DOI
- Segerer, 2004, CXCR3 is involved in tubulointerstitial injury in human glomerulonephritis, Am. J. Pathol., 164, 635, 10.1016/S0002-9440(10)63152-5 · DOI
- Karin, 2016, Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets, J. Leukoc. Biol., 99, 857, 10.1189/jlb.2MR0915-441R · DOI
- Afzali, 2007, The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease, Clin. Exp. Immunol., 148, 32, 10.1111/j.1365-2249.2007.03356.x · DOI · Paper page
- Stockinger, 2017, The dichotomous nature of T helper 17 cells, Nat. Rev. Immunol., 17, 535, 10.1038/nri.2017.50 · DOI
- Genovese, 2014, The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?, Fibrogenesis Tissue Repair, 7, 4, 10.1186/1755-1536-7-4 · DOI
- Kolset, 2012, Diabetic nephropathy and extracellular matrix, J. Histochem. Cytochem., 60, 976, 10.1369/0022155412465073 · DOI
- Moreth, 2014, Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury, Matrix Biol., 35, 143, 10.1016/j.matbio.2014.01.010 · DOI
- Iozzo, 2015, Proteoglycan form and function: a comprehensive nomenclature of proteoglycans, Matrix Biol., 42, 11, 10.1016/j.matbio.2015.02.003 · DOI
- Schaefer, 2001, Small proteoglycans in human diabetic nephropathy: discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin, FASEB J., 15, 559, 10.1096/fj.00-0493fje · DOI
- Thompson, 2011, Renal accumulation of biglycan and lipid retention accelerates diabetic nephropathy, Am. J. Pathol., 179, 1179, 10.1016/j.ajpath.2011.05.016 · DOI
- Hsieh, 2014, Soluble biglycan as a biomarker of inflammatory renal diseases, Int. J. Biochem. Cell Biol., 54, 223, 10.1016/j.biocel.2014.07.020 · DOI
- Babelova, 2009, Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors, J. Biol. Chem., 284, 24035, 10.1074/jbc.M109.014266 · DOI
- Zeng-Brouwers, 2014, De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways, Matrix Biol., 35, 132, 10.1016/j.matbio.2013.12.003 · DOI
- Hsieh, 2017, Biglycan- and sphingosine Kinase-1 signaling crosstalk regulates the synthesis of macrophage chemoattractants, Int. J. Mol. Sci., 18, 10.3390/ijms18030595 · DOI
- Hsieh, 2016, Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1beta synthesis, Matrix Biol., 49, 61, 10.1016/j.matbio.2015.12.005 · DOI
- Nastase, 2017, Signaling at the crossroads: matrix-derived proteoglycan and reactive oxygen species signaling, Antioxid. Redox Signal., 27, 855, 10.1089/ars.2017.7165 · DOI
- Eleazu, 2013, Review of the mechanism of cell death resulting from streptozotocin challenge in experimental animals, its practical use and potential risk to humans, J. Diabetes Metab. Disord., 12, 60, 10.1186/2251-6581-12-60 · DOI
- Sakata, 2012, Animal models of diabetes mellitus for islet transplantation, Exp. Diabetes Res., 2012, 256707, 10.1155/2012/256707 · DOI
- Sierro, 2007, Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7, Proc. Natl. Acad. Sci. U. S. A., 104, 14759, 10.1073/pnas.0702229104 · DOI
- Turner, 2010, CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis, J. Am. Soc. Nephrol., 21, 974, 10.1681/ASN.2009070741 · DOI
- Summers, 2009, Th1 and Th17 cells induce proliferative glomerulonephritis, J. Am. Soc. Nephrol., 20, 2518, 10.1681/ASN.2009030337 · DOI
- Coppieters, 2013, Functional redundancy of CXCR3/CXCL10 signaling in the recruitment of diabetogenic cytotoxic T lymphocytes to pancreatic islets in a virally induced autoimmune diabetes model, Diabetes, 62, 2492, 10.2337/db12-1370 · DOI
- Liu, 2006, Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3−/− mice with experimental autoimmune encephalomyelitis, J. Immunol., 176, 4399, 10.4049/jimmunol.176.7.4399 · DOI
- Lasch, 2015, Anti-CD3/anti-CXCL10 antibody combination therapy induces a persistent remission of type 1 diabetes in two mouse models, Diabetes, 64, 4198, 10.2337/db15-0479 · DOI
- Reininger, 1996, T helper cell subsets in the pathogenesis of systemic lupus erythematosus, Ann. Med. Intern. (Paris), 147, 467
- Van Raemdonck, 2015, CXCR3 ligands in disease and therapy, Cytokine Growth Factor Rev., 26, 311, 10.1016/j.cytogfr.2014.11.009 · DOI
- Enghard, 2009, CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients, Arthritis Rheum., 60, 199, 10.1002/art.24136 · DOI
- Okamoto, 2012, Kidney-infiltrating CD4+ T-cell clones promote nephritis in lupus-prone mice, Kidney Int., 82, 969, 10.1038/ki.2012.242 · DOI
- Cortes, 2008, Diabetes mellitus complicating systemic lupus erythematosus - analysis of the UCL lupus cohort and review of the literature, Lupus, 17, 977, 10.1177/0961203308091539 · DOI
- Dong, 2008, Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction, Kidney Int., 74, 1294, 10.1038/ki.2008.394 · DOI
- Paust, 2009, The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis, J. Am. Soc. Nephrol., 20, 969, 10.1681/ASN.2008050556 · DOI
- Tulone, 2011, Transferred antigen-specific T(H)17 but not T(H)1 cells induce crescentic glomerulonephritis in mice, Am. J. Pathol., 179, 2683, 10.1016/j.ajpath.2011.08.017 · DOI
- Azadegan-Dehkordi, 2015, The role of Th1 and Th17 cells in glomerulonephritis, J. Nephropathol., 4, 32
- Groom, 2011, CXCR3 ligands: redundant, collaborative and antagonistic functions, Immunol. Cell Biol., 89, 207, 10.1038/icb.2010.158 · DOI
- Tamassia, 2007, Molecular mechanisms underlying the synergistic induction of CXCL10 by LPS and IFN-gamma in human neutrophils, Eur. J. Immunol., 37, 2627, 10.1002/eji.200737340 · DOI
- Powell, 2004, Identification of the molecular mechanism by which TLR ligation and IFN-gamma synergize to induce MIG, Clin. Dev. Immunol., 11, 77, 10.1080/10446670410001670535 · DOI
- Horton, 1998, Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages, J. Biol. Chem., 273, 35088, 10.1074/jbc.273.52.35088 · DOI
- Kopydlowski, 1999, Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo, J. Immunol., 163, 1537, 10.4049/jimmunol.163.3.1537 · DOI
- Sheikh, 2014, An essential role for IFN-beta in the induction of IFN-stimulated gene expression by LPS in macrophages, J. Leukoc. Biol., 96, 591, 10.1189/jlb.2A0414-191R · DOI
- Majumder, 1998, p48/STAT-1alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alpha, J. Immunol., 161, 4736, 10.4049/jimmunol.161.9.4736 · DOI
- Coma, 2006, Treatment of monocytes with interleukin (IL)-12 plus IL-18 stimulates survival, differentiation and the production of CXC chemokine ligands (CXCL)8, CXCL9 and CXCL10, Clin. Exp. Immunol., 145, 535, 10.1111/j.1365-2249.2006.03145.x · DOI
- Lee-Sayer, 2015, The where, when, how, and why of hyaluronan binding by immune cells, Front. Immunol., 6, 150, 10.3389/fimmu.2015.00150 · DOI
- Esplugues, 2011, Control of TH17 cells occurs in the small intestine, Nature, 475, 514, 10.1038/nature10228 · DOI
- Li, 2013, Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages, Acta Biochim. Biophys. Sin., 45, 593, 10.1093/abbs/gmt049 · DOI
- Bianco, 1990, Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues, J. Histochem. Cytochem., 38, 1549, 10.1177/38.11.2212616 · DOI
- Kang, 2011, Structural biology of the toll-like receptor family, Annu. Rev. Biochem., 80, 917, 10.1146/annurev-biochem-052909-141507 · DOI
- Ng, 2011, Leucine-rich repeat (LRR) proteins: integrators of pattern recognition and signaling in immunity, Autophagy, 7, 1082, 10.4161/auto.7.9.16464 · DOI
- Matsushima, 2000, Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans–biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin, Proteins, 38, 210, 10.1002/(SICI)1097-0134(20000201)38:2<210::AID-PROT9>3.0.CO;2-1 · DOI
- Andrews, 2016, Small molecule CXCR3 antagonists, J. Med. Chem., 59, 2894, 10.1021/acs.jmedchem.5b01337 · DOI
- Xu, 1998, Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice, Nat. Genet., 20, 78, 10.1038/1746 · DOI
- Adachi, 1998, Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function, Immunity, 9, 143, 10.1016/S1074-7613(00)80596-8 · DOI
- Hoebe, 2003, Identification of Lps2 as a key transducer of MyD88-independent TIR signalling, Nature, 424, 743, 10.1038/nature01889 · DOI
- Dufour, 2002, IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking, J. Immunol., 168, 3195, 10.4049/jimmunol.168.7.3195 · DOI · Paper page
Cited by
Sorted by citations
Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis
Li, X., Zang, Y., Li, X., Sheng, T., Liu, S., Chen, L., Xu, X., Wang, L., Long, R., Zhang, M., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-73278-8 · Cited by 1
Metadata
- Authors
- Nastase, M. V., Zeng-Brouwers, J., Beckmann, J., Tredup, C., Christen, U., Radeke, H. H., Wygrecka, M., & Schaefer, L.
- Venue
- Matrix Biology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 68-69
- Pages
- 293-317
- ISSN
- 0945-053X
- Cited by
- 60
- References
- 4
- Language
- en
- Update notices
- erratum (2026-06-01)
- Funders
- German Research Council (SFB 815, SFB 1039, SFB 1177, SCHA 1082/6-1, WY119/1-3)
- German Center for Lung Research
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review