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.

  • Article
  • Published:

Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria

Nature Immunology volume 6, pages 989–994 (2005)Cite this article

Abstract

T cell–independent type 1 agonists such as Gram-negative bacterial lipopolysaccharides can stimulate B lymphocytes to proliferate and produce antibodies by signaling through Toll-like receptors. This phenomenon is well established in vitro, yet polyclonal B cell responses after bacterial infection in vivo are often weak and short-lived. We show here that B cell proliferation and polyclonal antibody production in response to Gram-negative bacterial infection are modulated by acyloxyacyl hydrolase, a host enzyme that deacylates bacterial lipopolysaccharides. Deacylation of lipopolysaccharide occurred over several days, allowing lipopolysaccharide to act as an innate immune stimulant yet limiting the eventual amount of B cell proliferation and polyclonal antibody production. Control of lipopolysaccharide activation by acyloxyacyl hydrolase indicates that mammals can regulate immune responses to bacterial infection by chemical modification of a Toll-like receptor agonist.

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: AOAH modulates antibody responses to Gram-negative bacterial infection.
Figure 2: AOAH limits LPS-induced polyclonal antibody production.
Figure 3: LPS-induced antibody synthesis requires TLR4 and intact LPS.
Figure 4: Differential in vitro responsiveness of B cells.
Figure 5: AOAH reduces LPS-induced B lymphocyte proliferation in vivo.
Figure 6: Multiple doses of LPS can mimic AOAH deficiency.
Figure 7: AOAH does not diminish LPS adjuvanticity.

Similar content being viewed by others

References

  1. Erwin, A.L. & Munford, R.S. Deacylation of structurally diverse lipopolysaccharides by human acyloxyacyl hydrolase. J. Biol. Chem. 265, 16444–16449 (1990).

    CAS  Google Scholar 

  2. Kitchens, R.L., Ulevitch, R.J. & Munford, R.S. Lipopolysaccharide (LPS) partial structures inhibit responses to LPS in a human macrophage cell line without inhibiting LPS uptake by a CD14-mediated pathway. J. Exp. Med. 176, 485–494 (1992).

    Article  CAS  Google Scholar 

  3. Munford, R.S. & Hall, C.L. Detoxification of bacterial lipopolysaccharides (endotoxins) by a human neutrophil enzyme. Science 234, 203–205 (1986).

    Article  CAS  Google Scholar 

  4. Luchi, M. & Munford, R.S. Binding, internalization, and deacylation of bacterial lipopolysaccharides by human neutrophils. J. Immunol. 151, 959–969 (1993).

    CAS  Google Scholar 

  5. Katz, S.S., Weinrauch, Y., Munford, R.S., Elsbach, P. & Weiss, J. Deacylation of lipopolysaccharide in whole Escherichia coli during destruction by cellular and extracellular components of a rabbit inflammatory peritoneal exudate. J. Biol. Chem. 274, 36579–36584 (1999).

    Article  CAS  Google Scholar 

  6. Lu, M. et al. Stimulus-dependent deacylation of bacterial lipopolysaccharide by dendritic cells. J. Exp. Med. 197, 1745–1754 (2003).

    Article  CAS  Google Scholar 

  7. Ochsenbein, A.F. & Zinkernagel, R. Natural antibodies and complement link innate and acquired immunity. Immunol. Today 21, 624–630 (2000).

    Article  CAS  Google Scholar 

  8. Boes, M. Role of natural and immune IgM antibodies in immune responses. Mol. Immunol. 37, 1141–1149 (2000).

    Article  CAS  Google Scholar 

  9. Nagai, Y. et al. The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes. J. Immunol. 174, 7043–7049 (2005).

    Article  CAS  Google Scholar 

  10. Coutinho, A., Moller, G. & Gronowicz, E. Genetical control of B-cell responses. IV. Inheritance of the unresponsiveness to lipopolysaccharides. J. Exp. Med. 142, 253–258 (1975).

    Article  CAS  Google Scholar 

  11. Watson, J. & Riblet, R. Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic responses to lipopolysaccharides. J. Exp. Med. 140, 1147–1161 (1974).

    Article  CAS  Google Scholar 

  12. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  Google Scholar 

  13. Krieg, A.M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).

    Article  CAS  Google Scholar 

  14. Dziarski, R. Recognition of bacterial peptidoglycan by the innate immune system. Cell. Mol. Life Sci. 60, 1793–1804 (2003).

    Article  CAS  Google Scholar 

  15. Massari, P. et al. Cutting edge: Immune stimulation by neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168, 1533–1537 (2002).

    Article  CAS  Google Scholar 

  16. Coutinho, A., Gronowicz, E., Bullock, W.W. & Moller, G. Mechanism of thymus-independent immunocyte triggering. Mitogenic activation of B cells results in specific immune responses. J. Exp. Med. 139, 74–92 (1974).

    Article  CAS  Google Scholar 

  17. Dziarski, R. Preferential induction of autoantibody secretion in polyclonal activation by peptidoglycan and lipopolysaccharide. II. In vivo studies. J. Immunol. 128, 1026–1030 (1982).

    CAS  Google Scholar 

  18. Dziarski, R. Studies on the mechanism of peptidoglycan- and lipopolysaccharide-induced polyclonal activation. Infect. Immun. 35, 507–514 (1982).

    CAS  Google Scholar 

  19. Preston, A., Mandrell, R.E., Gibson, B.W. & Apicella, M.A. The lipooligosaccharides of pathogenic gram-negative bacteria. Crit. Rev. Microbiol. 22, 139–180 (1996).

    Article  CAS  Google Scholar 

  20. Erwin, A.L., Mandrell, R.E. & Munford, R.S. Enzymatically deacylated Neisseria LPS inhibits murine splenocyte mitogenesis induced by LPS. Infect. Immun. 59, 1881–1887 (1991).

    CAS  Google Scholar 

  21. Van der Ley, P. et al. Modification of lipid A biosynthesis in Neisseria meningitidis lpxL mutants: influence on lipopolysaccharide structure, toxicity, and adjuvant activity. Infect. Immun. 69, 5981–5990 (2001).

    Article  CAS  Google Scholar 

  22. Munford, R.S. Detoxifying endotoxin: time, place, person. J. Endotoxin Res. 11, 69–84 (2005).

    CAS  Google Scholar 

  23. Cross, A.S. Endotoxin tolerance — current concepts in historical perspective. J. Endotoxin Res. 8, 83–98 (2002).

    CAS  Google Scholar 

  24. Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A. Negative regulation of Toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    Article  CAS  Google Scholar 

  25. Upton, C. & Buckley, J.T. A new family of lipolytic enzymes? Trends Biochem. Sci. 20, 178–179 (1995).

    CAS  Google Scholar 

  26. Munford, R.S., Sheppard, P.O. & O'Hara, P.J. Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J. Lipid Res. 36, 1653–1663 (1995).

    CAS  Google Scholar 

  27. Feulner, J.A. et al. Identification of acyloxyacyl hydrolase, a lipopolysaccharide-detoxifying enzyme, in the murine urinary tract. Infect. Immun. 72, 3171–3178 (2004).

    Article  CAS  Google Scholar 

  28. Cody, M.J. et al. Effect of inflammatory and anti-inflammatory stimuli on acyloxyacyl hydrolase gene expression and enzymatic activity in murine macrophages. J. Endotoxin Res. 4, 371–379 (1997).

    Article  CAS  Google Scholar 

  29. Forestier, C. et al. Interaction of Brucella abortus lipopolysaccharide with major histocompatibility complex class II molecules in B lymphocytes. Infect. Immun. 67, 4048–4054 (1999).

    CAS  Google Scholar 

  30. Weinrauch, Y., Katz, S.S., Munford, R.S., Elsbach, P. & Weiss, J. Deacylation of purified LPS by cellular and extracellular components of a sterile rabbit peritoneal inflammatory exudate. Infect. Immun. 67, 3376–3382 (1999).

    CAS  Google Scholar 

  31. Snapper, C.M., Rosas, F.R., Kehry, M.R., Mond, J.J. & Wetzler, L.M. Neisserial porins may provide critical second signals to polysaccharide-activated murine B cells for induction of immunoglobulin secretion. Infect. Immun. 65, 3203–3208 (1997).

    CAS  Google Scholar 

  32. Bhasin, N., Ho, Y. & Wetzler, L.M. Neissetia meningitides lipopolysaccharide modulates the specific humoral immune response to neisserial porins but has no effect on porin-induced upregulation of costimulatory ligand B7–2. Infect. Immun. 69, 5031–5036 (2001).

    Article  CAS  Google Scholar 

  33. Zinkernagel, R. & Hengartner, H. Regulation of the immune response by antigen. Science 293, 251–253 (2001).

    Article  CAS  Google Scholar 

  34. Uhr, J.W. & Möller, G. Regulatory effect of antibody on the immune response. Adv. Immunol. 8, 81–127 (1968).

    Article  CAS  Google Scholar 

  35. Takai, T., Ono, M., Hikida, M., Ohmori, H. & Ravetch, J.V. Augmented humoral and anaphylactic responses in FcγRII-deficient mice. Nature 379, 346–349 (1996).

    Article  CAS  Google Scholar 

  36. Heyman, B. Feedback regulation by IgG antibodies. Immunol. Lett. 88, 157–161 (2003).

    Article  CAS  Google Scholar 

  37. Medzhitov, R. & Janeway, C.A. Innate immunity: impact on the adaptive immune response. Curr. Opin. Immunol. 9, 4–9 (1997).

    Article  CAS  Google Scholar 

  38. Martin, F. & Kearney, J.F. B1 cells: similarities and differences with other B cell subsets. Curr. Opin. Immunol. 13, 195–201 (2001).

    Article  CAS  Google Scholar 

  39. Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004).

    Article  CAS  Google Scholar 

  40. Stoll, L.L., Denning, G.M. & Weintraub, N.L. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 2227–2236 (2004).

    Article  CAS  Google Scholar 

  41. Douwes, J., Pearce, N. & Heederik, D. Does environmental endotoxin exposure prevent asthma? Thorax 57, 86–90 (2002).

    Article  CAS  Google Scholar 

  42. Liu, A.H. Endotoxin exposure in allergy and asthma: Reconciling a paradox. J. Allergy Clin. Immunol. 109, 379–392 (2002).

    Article  CAS  Google Scholar 

  43. Nagy, L.E. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp. Biol. Med. 228, 882–890 (2003).

    Article  CAS  Google Scholar 

  44. Saito, H. & Ishii, H. Recent understanding of immunological aspects in alcoholic hepatitis. Hepatol. Res. 30, 193–198 (2004).

    Article  CAS  Google Scholar 

  45. Giardina, P.C. et al. Construction of acetate auxotrophs of Neisseria meningitidis to study host-meningococcal endotoxin interactions. J. Biol. Chem. 276, 5883–5891 (2001).

    Article  CAS  Google Scholar 

  46. Manthey, C.L. & Vogel, S.N. Elimination of trace endotoxin protein from rough chemotype LPS. J. Endotoxin Res. 1, 84–91 (1994).

    Article  CAS  Google Scholar 

  47. Munford, R.S. & Erwin, A.L. Eucaryotic lipopolysaccharide deacylating enzyme. Methods Enzymol. 209, 485–492 (1992).

    Article  CAS  Google Scholar 

  48. Poltorak, A., Smirnova, I., Clisch, R. & Beutler, B. Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice. J. Endotoxin Res. 6, 51–56 (2000).

    Article  CAS  Google Scholar 

  49. Wilder, J.A., Koh, C.Y. & Yuan, D. The role of NK cells during In vivo antigen-specific antibody responses. J. Immunol. 156, 146–152 (1996).

    CAS  Google Scholar 

  50. Mohan, C., Adams, S., Stanik, V. & Datta, S.K. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177, 1367–1381 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Kitchens, R. Dziarski and L. Wetzler for advice. Supported by the National Institutes of Health (AI18188 and AI44642) and by the Jan and Henri Bromberg Chair in Internal Medicine (The University of Texas Southwestern Medical Center).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Mingfang Lu, Mei Zhang, Xiang-Hong Li & Robert S Munford

  2. Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Akira Takashima

  3. Department of Internal Medicine and Department of Microbiology, University of Iowa, Iowa City, 52242, Iowa, USA

    Jerrold Weiss & Michael A Apicella

  4. Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Dorothy Yuan

  5. Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Robert S Munford

Authors
  1. Mingfang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akira Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jerrold Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael A Apicella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang-Hong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dorothy Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert S Munford
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert S Munford.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, M., Zhang, M., Takashima, A. et al. Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria. Nat Immunol 6, 989–994 (2005). https://doi.org/10.1038/ni1246

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1246

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing