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Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105

Nature Immunology volume 6, pages 571–578 (2005)Cite this article

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Abstract

Activation of Toll-like receptor (TLR) signaling by microbial signatures is critical to the induction of immune responses. Such responses demand tight regulation. RP105 is a TLR homolog thought to be mostly B cell specific, lacking a signaling domain. We report here that RP105 expression was wide, directly mirroring that of TLR4 on antigen-presenting cells. Moreover, RP105 was a specific inhibitor of TLR4 signaling in HEK 293 cells, a function conferred by its extracellular domain. Notably, RP105 and its helper molecule, MD-1, interacted directly with the TLR4 signaling complex, inhibiting its ability to bind microbial ligand. Finally, RP105 regulated TLR4 signaling in dendritic cells as well as endotoxin responses in vivo. Thus, our results identify RP105 as a physiological negative regulator of TLR4 responses.

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Figure 1: RP105 expression by human peripheral blood leukocytes.
Figure 2: RP105 expression by mouse leukocytes.
Figure 3: Dose-dependent suppression of TLR4 signaling in HEK 293 cells by RP105 expression.
Figure 4: Specificity of RP105-mediated suppression.
Figure 5: The extracellular domain of RP105 is sufficient to effect suppression of TLR4 signaling.
Figure 6: RP105–MD-1 interacts directly with TLR4–MD-2.
Figure 7: RP105–MD-1 inhibit binding of LPS to TLR4–MD-2.
Figure 8: Altered TLR4-induced cytokine production by DCs from RP105-deficient mice.
Figure 9: Ability of heterologous TLR signaling to overcome RP105-mediated inhibition of TLR4 signaling.
Figure 10: Exaggerated in vivo responses to LPS in RP105-deficient mice.

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Change history

  • 26 April 2005

    changed myD88 to MyD88s in body of article; and added full legends to supplementary information

Notes

  1. NOTE: In the version originally published online, the supplementary figures lacked complete legends. The full legends are now included with the figures. This correction has been appended to the PDF version online.

  2. NOTE: In the version originally published online, the fourth sentence of the second paragraph of the Discussion section misidentified the negative regulator “MyD88s.” The sentence should read as follows: "Several direct, negative regulators of TLR signaling have also been found, including SIGIRR33, IRAK-M37, MyD88s38, Tollip39, ST2 (ref. 28), Nod2 (ref. 40) and Triad3A41." This error has been corrected for the HTML version of this article online. The correction has been appended to the PDF version online.

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Acknowledgements

The authors thank L. Flick, and H. Stanley for technical assistance; and C. Chougnet, J. Bridges, K. Fitzgerald, B. Aronow, B. Sakthivel and J. Meller for discussions. Supported by the National Institutes of Health (R21 AI063183 to C.L.K., and T32 AI 055406).

Author information

Author notes

  1. Aurelien Trompette, Sowsan F Atabani and Rajat Madan: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Senad Divanovic, Aurelien Trompette, Sowsan F Atabani, Rajat Madan, Yasmine Belkaid & Christopher L Karp

  2. Division of Infectious Diseases & Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    Douglas T Golenbock, Alberto Visintin, Robert W Finberg & Evelyn A Kurt-Jones

  3. Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, 10021, New York, USA

    Alexander Tarakhovsky

  4. Department of Microbiology and Immunology and Department of Medicine, University of Maryland-Baltimore, Baltimore, 21201, Maryland, USA

    Stefanie N Vogel

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Supplementary information

Supplementary Fig. 1

RP105 phylogeny. (PDF 127 kb)

Supplementary Fig. 2

MD-1 expression is necessary for RP105-mediated suppression of TLR4 signaling. (PDF 364 kb)

Supplementary Fig. 3

RP105 fails to inhibit NF-κB transactivation driven by overexpression of TLR4 signaling molecules. (PDF 216 kb)

Supplementary Fig. 4

MD-1 and MD-2 can interact directly with each other. (PDF 437 kb)

Supplementary Fig. 5

Similar expression of molecules regulating TLR signaling in bone marrow-derived dendritic cells from RP105-deficient and wild-type mice. (PDF 315 kb)

Supplementary Fig. 6

Altered TLR4-induced cytokine production by resident peritoneal macrophages from RP105-deficient mice. (PDF 164 kb)

Supplementary Fig. 7

Regulation of RP105 expression by LPS. DC were stimulated with purified E. coli K235 LPS. (PDF 202 kb)

Supplementary Fig. 8

Genotyping and phenotyping of RP105-deficient mice. (PDF 479 kb)

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Divanovic, S., Trompette, A., Atabani, S. et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol 6, 571–578 (2005). https://doi.org/10.1038/ni1198

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