Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

TLR3-dependent immune regulatory functions of human mesangial cells

Cellular & Molecular Immunology volume 9, pages 334–340 (2012)Cite this article

Abstract

In glomerulonephritis, the migration of inflammatory cells into the glomerulus is an important step in disease initiation and progression. The viral receptor Toll-like receptor 3 (TLR3) is known to play a role in virus-associated glomerulonephritis. Based on this knowledge, this study aimed to define the effects of the TLR3 ligand polyriboinosinic:polyribocytidylic acid (poly(I:C)) on the expression of adhesion molecules and macrophage colony-stimulating factor (M-CSF) on resident glomerular cells. Experiments in MCs demonstrated that the activation of viral receptors by poly(I:C) leads to a time- and dose-dependent induction of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and M-CSF at both the mRNA and protein levels; these results were confirmed by incubating MCs with HCV RNA. As shown in knockdown experiments, this effect is specifically mediated by TLR3. The prestimulation of MCs with proinflammatory cytokines increases the effects of poly(I:C), except for its induction of VCAM-1. Tumor-necrosis factor (TNF)-α, likewise, induces ICAM-1, VCAM-1 and M-CSF, and amplifies the mesangial response to poly(I:C). These results were confirmed by incubating MCs with HCV RNA. We thus provide evidence that human MCs represent a potential target of the leukocytes and monocytes that infiltrate the glomerulus in viral disease-associated GN, highlighting the possibility that MCs may act as resident antigen-presenting cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Chadban SJ, Tesch GH, Foti R, Lan HY, Atkins RC, Nikolic-Paterson DJ . Interleukin-10 differentially modulates MHC class II expression by mesangial cells and macrophages in vitro and in vivo. Immunology 1998; 94: 72–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Radeke HH, Resch K . The inflammatory function of renal glomerular mesangial cells and their interaction with the cellular immune system. Clin Investig 1992; 70: 825–842.

    Article  CAS  PubMed  Google Scholar 

  3. Stokes MB, Chawla H, Brody RI, Kumar A, Gertner R, Goldfarb DS et al. Immune complex glomerulonephritis in patients coinfected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis 1997; 29: 514–525.

    Article  CAS  PubMed  Google Scholar 

  4. Okada K, Takishita Y, Shimomura H, Tsuji T, Miyamura T, Kuhara Ts et al. Detection of hepatitis C virus core protein in the glomeruli of patients with membranous glomerulonephritis. Clin Nephrol 1996; 45: 71–76.

    CAS  PubMed  Google Scholar 

  5. Yamabe H, Inuma H, Osawa H, Kaizuka M, Tamura N, Tsunoda S et al. Glomerular deposition of hepatitis C virus in membranoproliferative glomerulonephritis. Nephron 1996; 72: 741.

    Article  CAS  PubMed  Google Scholar 

  6. Lamprecht P, Moosig F, Gause A, Herlyn K, Csernok E, Hansen H et al. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2001; 60: 385–390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaplanski G, Maisonobe T, Marin V, Grès S, Robitail S, Farnarier C et al. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in the pathogenesis of severe forms of vasculitis due to hepatitis C-associated mixed cryoglobulinemia. J Hepatol 2005; 42: 334–340.

    Article  CAS  PubMed  Google Scholar 

  8. Wörnle M, Schmid H, Banas B, Merkle M, Henger A, Roeder M et al. Novel role of Toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 2006; 168: 370–385.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wörnle M, Roeder M, Sauter M, Merkle M, Ribeiro A . Effect of dsRNA on mesangial cell synthesis of plasminogen activator inhibitor type 1 and tissue plasminogen activator. Nephron Exp Nephrol 2009; 113: 57–65.

    Article  Google Scholar 

  10. Wörnle M, Roeder M, Sauter M, Ribeiro A . Role of matrix metalloproteinases in viral-associated glomerulonephritis. Nephrol Dial Transplant 2009; 24: 1113–1121.

    Article  PubMed  Google Scholar 

  11. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA . Recognition of double-stranded RNA and activation of NF-κB by toll-like receptor 3. Nature 2001; 413: 732–738.

    Article  CAS  Google Scholar 

  12. Banas B, Wörnle M, Berger T, Nelson PJ, Cohen CD, Kretzler M et al. Roles of SLC/CCL21 and CCR7 in human kidney for mesangial proliferation, migration, apoptosis, and tissue homeostasis. J Immunol 2002; 168: 4301–4307.

    Article  CAS  PubMed  Google Scholar 

  13. Matsukura S, Kokubu F, Kurokawa M, Kawaguchi M, Ieki K, Kuga H et al. Role of RIG-I, MDA-5, and PKR on the expression of inflammatory chemokines induced by synthetic dsRNA in airway epithelial cells. Int Arch of Allergy Immunol 2007; 143 Suppl 1: 80–83.

    Article  CAS  Google Scholar 

  14. Merkle M, Ribeiro A, Wörnle M . TLR3 dependent regulation of cytokines in human mesangial cells: a novel role for IP-10 and TNFa in hepatitis C associated glomerulonephritis. Am J Physiol Renal Physiol 2011; 301: 57–69.

    Article  Google Scholar 

  15. Muller WA . Mechanisms of transendothelial migration of leukocytes. Circ Res 2009; 105: 223–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wittchen ES . Endothelial signaling in paracellular and transcellular leukocyte transmigration. Front Biosci 2009; 14: 2522–2545.

    Article  CAS  PubMed Central  Google Scholar 

  17. Metcalf D . The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 1986; 67: 257–267.

    CAS  PubMed  Google Scholar 

  18. Nguyen TT, Shou I, Funabiki K, Shirato I, Kubota K, Tomino Y . Correlations among expression of glomerular intercellular adhesion molecule 1 (ICAM-1), levels of serum soluble ICAM-1, and renal histopathology in patients with IgA nephropathy. Am J Nephrol 1999; 19: 495–499.

    Article  CAS  PubMed  Google Scholar 

  19. Arrizabalaga P, Solé M, Abellana R, de las Cuevas X, Soler J, Pascual J et al. Tubular and interstitial expression of ICAM-1 as a marker of renal injury in IgA nephropathy. Am J Nephrol 2003; 23: 121–128.

    Article  CAS  PubMed  Google Scholar 

  20. Ashizawa M, Miyazaki M . Detection of nuclear factor-kappaB in IgA nephropathy using Southwestern histochemistry. Am J Kidney Dis 2003; 42: 76–86.

    Article  CAS  PubMed  Google Scholar 

  21. Lefkowith JB . Leukocyte migration in immune complex glomerulonephritis: role of adhesion receptors. Kidney Int 1997; 51: 1469–1475.

    Article  CAS  PubMed  Google Scholar 

  22. Moon KC, Park SY, Kim HW, Hong HK, Lee HS . Expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human crescentic glomerulonephritis. Histopathology 2002; 41: 158–165.

    Article  CAS  PubMed  Google Scholar 

  23. Arrizabalaga P, Solé M, Iglesias C, Escaramís G, Ascaso C . Renal expression of ICAM-1 and VCAM-1 in ANCA-associated glomerulonephritis—are there differences among serologic subgroups? Clin Nephrol 2006; 65: 79–86.

    Article  CAS  PubMed  Google Scholar 

  24. Park CW, Kim JH, Lee JH, Kim YS, Ahn HJ, Shin YS et al. High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappa B-dependent. Diabetologia 2000; 43: 1544–1553.

    Article  CAS  PubMed  Google Scholar 

  25. Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003; 52: 2586–2593.

    Article  CAS  PubMed  Google Scholar 

  26. Ma J, Möllsten A, Prázny M, Falhammar H, Brismar K, Dahlquist G et al. 2006. Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy. Diabet Med 2005; 23: 1093–1099.

    Article  Google Scholar 

  27. Crook ED, Penumalee S, Gavini B, Filippova K . Hepatitis C is a predictor of poorer renal survival in diabetic patients. Diabetes Care 2005; 28: 2187–2191.

    Article  PubMed  Google Scholar 

  28. Wiggins JE, Patel SR, Shedden KA, Goyal M, Wharram BL, Martini S et al. NFkappaB promotes inflammation, coagulation, and fibrosis in the aging glomerulus. J Am Soc Nephrol 2010; 21: 587–597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jiang Z, Zamanian-Daryoush M, Nie H, Silva AM, Williams BR, Li X . Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR. J Biol Chem 2003; 278: 16713–16719.

    Article  CAS  PubMed  Google Scholar 

  30. Luft FC, Mervaala E, Müller DN, Gross V, Schmidt F, Park JK et al. Hypertension-induced end-organ damage: A new transgenic approach to an old problem. Hypertension 1999; 33: 212–218.

    Article  CAS  PubMed  Google Scholar 

  31. Riser BL, Varani J, Cortes P, Yee J, Dame M, Sharba AK . Cyclic stretching of mesangial cells upregulates intercellular adhesion molecule-1 and leukocyte adherence: a possible new mechanism for glomerulosclerosis. Am J Pathol 2001; 158: 11–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Radeke HH, Emmendörffer A, Uciechowski P, von der Ohe J, Schwinzer B, Resch K . Activation of autoreactive T-lymphocytes by cultured syngeneic glomerular mesangial cells. Kidney Int 1994; 45: 763–774.

    Article  CAS  PubMed  Google Scholar 

  33. Uciechowski P, Schwarz M, Gessner JE, Schmidt RE, Resch K, Radeke HH . IFN-gamma induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells. Eur J Immunol 1998; 28: 2928–2935.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Deutsche Vereinigung zur Bekämpfung von Viruskrankheiten, the Else Kröner-Fresenius-Stiftung, the Wilhelm-Vaillant-Stiftung and the Fritz Bender Stiftung to MW.

Author information

Authors and Affiliations

  1. Medizinische Poliklinik—Campus Innenstadt, Klinikum der LMU, Munich, Germany

    Monika Merkle, Andrea Ribeiro, Simone Köppel, Maximilian Roeder & Markus Wörnle

  2. Walter-Brendel-Centre of Experimental Medicine, University of Munich, Munich, Germany

    Joachim Pircher & Hanna Mannell

Authors
  1. Monika Merkle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simone Köppel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joachim Pircher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hanna Mannell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maximilian Roeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Markus Wörnle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Wörnle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Merkle, M., Ribeiro, A., Köppel, S. et al. TLR3-dependent immune regulatory functions of human mesangial cells. Cell Mol Immunol 9, 334–340 (2012). https://doi.org/10.1038/cmi.2012.3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2012.3

Keywords

This article is cited by

Search

Advanced search

Quick links