CD14 Controls the LPS-induced Endocytosis of Toll-like Receptor 4

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Nov 15

PMID 22078883

Citations 482

Authors

Ivan Zanoni

Renato Ostuni

Lorri R Marek

Simona Barresi

Roman Barbalat

Gregory M Barton

Francesca Granucci

Jonathan C Kagan

Affiliations

Soon will be listed here.

Abstract

The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction.

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References

Platt C, Ma J, Chalouni C, Ebersold M, Bou-Reslan H, Carano R . Mature dendritic cells use endocytic receptors to capture and present antigens. Proc Natl Acad Sci U S A. 2010; 107(9):4287-92. PMC: 2840134. DOI: 10.1073/pnas.0910609107. View

Underhill D, Rossnagle E, Lowell C, Simmons R . Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005; 106(7):2543-50. PMC: 1895265. DOI: 10.1182/blood-2005-03-1239. View

Rogers N, Slack E, Edwards A, Nolte M, Schulz O, Schweighoffer E . Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005; 22(4):507-17. DOI: 10.1016/j.immuni.2005.03.004. View

Cheong C, Matos I, Choi J, Dandamudi D, Shrestha E, Longhi M . Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010; 143(3):416-29. PMC: 3150728. DOI: 10.1016/j.cell.2010.09.039. View

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

Latz E, Visintin A, Lien E, Fitzgerald K, Espevik T, Golenbock D . The LPS receptor generates inflammatory signals from the cell surface. J Endotoxin Res. 2004; 9(6):375-80. DOI: 10.1179/096805103225003303. View

Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S . CD14 is required for MyD88-independent LPS signaling. Nat Immunol. 2005; 6(6):565-70. DOI: 10.1038/ni1207. View

Barton G, Kagan J . A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol. 2009; 9(8):535-42. PMC: 3934928. DOI: 10.1038/nri2587. View

Zaru R, Ronkina N, Gaestel M, Arthur J, Watts C . The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nat Immunol. 2007; 8(11):1227-35. DOI: 10.1038/ni1517. View

10.

Kagan J, Su T, Horng T, Chow A, Akira S, Medzhitov R . TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol. 2008; 9(4):361-8. PMC: 4112825. DOI: 10.1038/ni1569. View

11.

Kagan J, Medzhitov R . Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell. 2006; 125(5):943-55. DOI: 10.1016/j.cell.2006.03.047. View

12.

Moore K, Andersson L, Ingalls R, Monks B, Li R, Arnaout M . Divergent response to LPS and bacteria in CD14-deficient murine macrophages. J Immunol. 2000; 165(8):4272-80. DOI: 10.4049/jimmunol.165.8.4272. View

13.

Akira S, Takeda K . Toll-like receptor signalling. Nat Rev Immunol. 2004; 4(7):499-511. DOI: 10.1038/nri1391. View

14.

West M, Wallin R, Matthews S, Svensson H, Zaru R, Ljunggren H . Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling. Science. 2004; 305(5687):1153-7. DOI: 10.1126/science.1099153. View

15.

Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X . Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282(5396):2085-8. DOI: 10.1126/science.282.5396.2085. View

16.

Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y . Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999; 162(7):3749-52. View

17.

Husebye H, Halaas O, Stenmark H, Tunheim G, Sandanger O, Bogen B . Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J. 2006; 25(4):683-92. PMC: 1383569. DOI: 10.1038/sj.emboj.7600991. View

18.

Depoil D, Weber M, Treanor B, Fleire S, Carrasco Y, Harwood N . Early events of B cell activation by antigen. Sci Signal. 2009; 2(63):pt1. DOI: 10.1126/scisignal.263pt1. View

19.

Drutman S, Trombetta E . Dendritic cells continue to capture and present antigens after maturation in vivo. J Immunol. 2010; 185(4):2140-6. PMC: 2928255. DOI: 10.4049/jimmunol.1000642. View

20.

Underhill D, Ozinsky A, Hajjar A, Stevens A, Wilson C, Bassetti M . The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999; 401(6755):811-5. DOI: 10.1038/44605. View