Role of CD14 in Lung Inflammation and Infection

  • A. Anas
  • T. Van Der Poll
  • A. F. De Vas
Conference paper


Toll-like receptors (TLR) on the surface of cells of the respiratory tract play an essential role in sensing the presence of microorganisms in the airways and lungs. These receptors trigger inflammatory responses, activate innate immune responses, and prime adaptive immune responses to eradicate invading microbes [1]. TLR are members of a family of pattern-recognition receptors, which recognize molecular structures of bacteria, viruses, fungi and protozoa (pathogen-associated molecular patterns or PAMPs), as well as endogenous structures and proteins released during inflammation (damage/danger-associated molecular patterns or DAMPs). To date, ten different TLR have been identified in humans and twelve in mice. TLR are expressed on all cells of the immune system, but also on parenchymal cells of many organs and tissues. The binding of a PAMP to a TLR results in cellular activation and initiates a variety of effector functions, including cytokine secretion, proliferation’ co-stimulation or phagocyte maturation. To facilitate microbial recognition and to amplify cellular responses, certain TLR require additional proteins, such as lipopolysaccharide (LPS) binding protein (LBP), CD14, CD36 and high mobility group box-l protein (HMGB-l). In this chapter, the role of CD14 as an accessory receptor for TLR in lung inflammation and infection is discussed. The central role of CD14 in the recognition of various PAMPs and amplification of immune and inflammatory responses in the lung is depicted in Fig. 1.

Fig. 1.

Central role of CD14 in pathogen- and pathogen-associated molecular pattern (PAMP)-induced responses in the lung. CD14, which lacks an intracellular domain for signal transduction, is expressed on the surface of alveolar macrophages, infiltrating monocytes and neutrophils, and at lower levels also on epithelial and endothelial cells in the lung. CD14 recognizes and binds various structures from invading microbes, such as lipopolysaccharide (LPS) from Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, lipoarabinomannan (LAM) from mycobacteria, viral double stranded (ds) RNA and F glycoprotein (F-gp) from respiratory syncytial virus (RSV). CD14 subsequently transfers these bound components to Toll-like receptors (TLR) which than trigger cell activation. Binding of LPS to CD14 is regulated by additional accessory receptors in the lung, including LPS-binding protein (LBP) and a number of surfactant proteins (SP). Furthermore, soluble CD14 (sCD14) enhances LPS-induced activation of cells with low CD14 expression. Depending on the microbe and the PAMPs it expresses, CD14-amplified responses can either be beneficial to the host by induction of an adequate inflammatory and immune response to eradicate the invading microbe, or detrimental to the host by excessive inflammation and/or dissemination of the pathogen.


Respiratory Syncytial Virus Respir Crit Lung Inflammation Neutrophil Influx Muramyl Dipeptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Basu S, Fenton MJ (2004) Toll-like receptors: function and roles in lung disease. Am J Physiol Lung Cell Mol Physiol 286:L887–L892CrossRefPubMedGoogle Scholar
  2. 2.
    Wright SD (1995) CD14 and innate recognition of bacteria. J Immunol 155: 6–8PubMedGoogle Scholar
  3. 3.
    LeVan TD, Von Essen S, Romberger DJ, et al (2005) Polymorphisms in the CD14 gene associated with pulmonary function in farmers. Am J Respir Crit Care Med 171: 773–779CrossRefPubMedGoogle Scholar
  4. 4.
    Kim JI, Lee CJ, Jin MS, et al (2005) Crystal structure of CD14 and its implications for lipopolysaccharide signaling. J Biol Chern 280: 11347–11351CrossRefGoogle Scholar
  5. 5.
    Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249: 1431–1433CrossRefPubMedGoogle Scholar
  6. 6.
    Martin TR, Rubenfeld GD, Ruzinski JT, et al (1997) Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory response in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 155: 937–944PubMedGoogle Scholar
  7. 7.
    Beutler B, Rietschel ET (2003) Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 3: 169–176CrossRefPubMedGoogle Scholar
  8. 8.
    Knapp S, Florquin S, Golenbock DT, Van der Poll T (2006) Pulmonary lipopolysaccharide (LPS)-binding protein inhibits the LPS-induced lung inflammation in vivo. J Immunol 176: 3189–3195PubMedGoogle Scholar
  9. 9.
    Pugin J, Schurer-Maly CC, Leturcq D, et al (1993) Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci USA 90: 2744–2748CrossRefPubMedGoogle Scholar
  10. 10.
    Kitchens RL, Thompson PA (2005) Modulatory effects of sCD14 and LBP on LPS-host cell interactions. J Endotoxin Res 11: 225–229PubMedGoogle Scholar
  11. 11.
    Park BS, Song DH, Kim HM, et al (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458: 1191–1195CrossRefPubMedGoogle Scholar
  12. 12.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124: 783–801CrossRefPubMedGoogle Scholar
  13. 13.
    Jiang Z, Georgel P, Du X, et al (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6: 565–570CrossRefPubMedGoogle Scholar
  14. 14.
    Kurt-Jones EA, Popova L, Kwinn L, et al (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1: 398–401CrossRefPubMedGoogle Scholar
  15. 15.
    Chaby R, Garcia-Verdugo I, Espinassous Q, Augusto LA (2005) Interactions between LPS and lung surfactant proteins. J Endotoxin Res 11: 181–185PubMedGoogle Scholar
  16. 16.
    Senft AP, Korfhagen TR, Whitsett JA, Shapiro SD, LeVine AM (2005) Surfactant protein-D regulates soluble CD14 through matrix metalloproteinase-12. J Immunol 174: 4953–4959PubMedGoogle Scholar
  17. 17.
    Pugin J, Heumann ID, Tomasz A, et al (1994) CD14 is a pattern recognition receptor. Immunity 1: 509–516CrossRefPubMedGoogle Scholar
  18. 18.
    Schroder NW, Morath S, Alexander C, et al (2003) Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)2, lipopolysaccharide-binding protein (LBP), and CDI4, whereas TLR-4 and MD-2 are not involved. J Biol Chem 278: 15587–15594CrossRefPubMedGoogle Scholar
  19. 19.
    Dziarski R, Gupta D (2005) Peptidoglycan recognition in innate immunity. J Endotoxin Res 11: 304–310PubMedGoogle Scholar
  20. 20.
    Lee HK, Dunzendorfer S, Soldau K, Tobias PS (2006) Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 24: 153–163CrossRefPubMedGoogle Scholar
  21. 21.
    Ishii Y,Wang Y, Haziot A, et al (1993) Lipopolysaccharide binding protein and CD 14 interaction induces tumor necrosis factor-alpha generation and neutrophil sequestration in lungs after intratracheal endotoxin. Circ Res 73: 15–23PubMedGoogle Scholar
  22. 22.
    Smith LS, Kajikawa O, Elson G, et al (2008) Effect of Toll-like receptor 4 blockade on pulmonary inflammation caused by mechanical ventilation and bacterial endotoxin. Exp Lung Res 34: 225–243CrossRefPubMedGoogle Scholar
  23. 23.
    Tasaka S, Ishizaka A, Yamada W, et al (2003) Effect of CD14 blockade on endotoxin-induced acute lung injury in mice. Am J Respir Cell Mol Biol 29: 252–258CrossRefPubMedGoogle Scholar
  24. 24.
    Ieyaseelan S, Chu HW, Young SK, Freeman MW, Worthen GS (2005) Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. Infect Immun 73: 1754–1763CrossRefGoogle Scholar
  25. 25.
    Knapp S, Wieland CW, Florquin S, et al (2006) Differential roles of CD14 and toll-like receptors 4 and 2 in murine Acinetobacter pneumonia. Am J Respir Crit Care Med 173: 122–129CrossRefPubMedGoogle Scholar
  26. 26.
    Brass DM, Hollingsworth JW, McElvania-Tekippe E, et al (2007) CD14 is an essential mediator of LPS induced airway disease. Am J Physiol Lung Cell Mol Physiol 293: L77–83CrossRefGoogle Scholar
  27. 27.
    Hollingsworth JW 2nd, Cook DN, Brass DM, et al (2004) The role of Toll-like receptor 4 in environmental airway injury in mice. Am J Respir Crit Care Med 170: 126–132CrossRefPubMedGoogle Scholar
  28. 28.
    Knapp S, von Aulock S, Leendertse M, et al (2008) Lipoteichoic acid-induced lung inflammation depends on TLR2 and the concerted action of TLR4 and the platelet-activating factor receptor. J Immunol 180: 3478–3484PubMedGoogle Scholar
  29. 29.
    Dessing MC, Schouten M, Draing C, et al (2008) Role played by Toll-like receptors 2 and 4 in lipoteichoic acid-induced lung inflammation and coagulation. J Infect Dis 197: 245–252CrossRefPubMedGoogle Scholar
  30. 30.
    Wieland CW, Florquin S, Maris NA, et al (2005) The MyD88-dependent, but not the MyD88independent, pathway of TLR4 signaling is important in clearing nontypeable haemophilus influenzae from the mouse lung. J Immunol 175: 6042–6049PubMedGoogle Scholar
  31. 31.
    Wang X, Moser C, Louboutin JP, et al (2002) Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. J Immunol 168: 810–815PubMedGoogle Scholar
  32. 32.
    Frevert CW, Matute-Bello G, Skerrett SJ, et al (2000) Effect of CD14 blockade in rabbits with Escherichia coli pneumonia and sepsis. J Immunol 164: 5439–5445PubMedGoogle Scholar
  33. 33.
    Lee JS, Frevert CW, Matute-Bello G, et al (2005) TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia. Am J Physiol Lung Cell Mol Physiol 289:L731–L738CrossRefPubMedGoogle Scholar
  34. 34.
    Jeyaseelan S, Young SK, Fessler MB, et al (2007) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia. J Immunol 178: 3153–3160PubMedGoogle Scholar
  35. 35.
    Cai S, Zemans RL, Young SK, Worthen GS, Jeyaseelan S (2009) Myeloid differentiation protein-2-dependent and-independent neutrophil accumulation during Escherichia coli pneumonia. Am J Respir Cell Mol Biol 40: 701–709CrossRefPubMedGoogle Scholar
  36. 36.
    Ramphal R, Balloy V, Jyot J, et al (2008) Control of Pseudomonas aeruginosa in the lung requires the recognition of either lipopolysaccharide or flagellin. J Immunol 181: 586–592PubMedGoogle Scholar
  37. 37.
    Reddi K, Phagoo SB, Anderson KD, Warburton D (2003) Burkholderia cepacia-induced IL-8 gene expression in an alveolar epithelial cell line: signaling through CD14 and mitogen-activated protein kinase. Pediatr Res 54: 297–305CrossRefPubMedGoogle Scholar
  38. 38.
    Branger J, Knapp S, Weijer S, et al (2004) Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infect Immun 72: 788–794CrossRefPubMedGoogle Scholar
  39. 39.
    Wiersinga WJ, Wieland CW, Dessing MC, et al (2007) Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis). PLoS Med 4: e248CrossRefPubMedGoogle Scholar
  40. 40.
    Wiersinga WJ, de Vos AF, Wieland CW, et al (2008) CD14 impairs host defense against gram-negative sepsis caused by Burkholderia pseudomallei in mice. J Infect Dis 198: 1388–1397CrossRefPubMedGoogle Scholar
  41. 41.
    Dessing MC, Knapp S, Florquin S, De Vos AF, Van der Poll T (2007) CD14 facilitates invasive respiratory tract infection by Streptococcus pneumoniae. Am J Respir Crit Care Med 175: 604–611CrossRefPubMedGoogle Scholar
  42. 42.
    Knapp S, Wieland CW, Murawskian’ t Veer C, et al (2004) Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J Immunol 172: 3132–3138PubMedGoogle Scholar
  43. 43.
    Rijneveld AW, Weijer S, Florquin S, et al (2004) Improved host defense against pneumococcal pneumonia in platelet-activating factor receptor-deficient mice. J Infect Dis 189: 711–716CrossRefPubMedGoogle Scholar
  44. 44.
    Wieland CW, Van der Windt GJ, Wiersinga WJ, Florquin S, Van der Poll T (2008) CD14 contributes to pulmonary inflammation and mortality during murine tuberculosis. Immunology 125: 272–279CrossRefPubMedGoogle Scholar
  45. 45.
    Reiling N, Holscher C, Fehrenbach A, et al (2002) Toll-like receptor (TLR)2-and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 169: 3480–3484PubMedGoogle Scholar
  46. 46.
    Abel B, Thieblemont N, Quesniaux VJ, et al (2002) Toll-like receptor 4 expression is required to control chronic Mycobacterium tuberculosis infection in mice. J Immunol 169: 3155–3162PubMedGoogle Scholar
  47. 47.
    Drennan MB, Nicolle D, Quesniaux VJ, et al (2004) Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. Am J Pathol 164: 49–57CrossRefPubMedGoogle Scholar
  48. 48.
    Branger J, Leemans IC, Florquin S, et al (2004) Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice. Int Immunol 16: 509–516CrossRefPubMedGoogle Scholar
  49. 49.
    Murawski MR, Bowen GN, Cerny AM, et al (2009) Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol 83: 1492–1500CrossRefPubMedGoogle Scholar
  50. 50.
    Dessing MC, Van der Sluijs KF, Florquin S, Van der Poll T (2007) CD14 plays a limited role during influenza A virus infection in vivo. Immunol Lett 113: 47–51CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2010

Authors and Affiliations

  • A. Anas
    • 1
  • T. Van Der Poll
    • 1
  • A. F. De Vas
    • 1
  1. 1.Center for Experimental and Molecular Medicine Center of infection and ImmunityAcademic Medical CenterAmsterdamNetherlands

Personalised recommendations