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NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens

Nature volume 488, pages 389–393 (2012)Cite this article

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Abstract

Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of nuclear factor-κB (NF-κB), type I interferon and inflammasome signalling1. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis2,3,4, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show that Nlrp6-deficient mice are highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase (MAPK) and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic NOD1/2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.

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Figure 1: Nlrp6 −/− mice are resistant to Listeria and Salmonella infection.
Figure 2: Enhanced monocyte and neutrophil recruitment in infected Nlrp6 −/− mice.
Figure 3: NLRP6 negatively regulates NF-κB and ERK signalling.
Figure 4: NLRP6 negatively regulates canonical NF-κB activation pathway.

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References

  1. Kanneganti, T. D., Lamkanfi, M. & Nunez, G. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007)

    Article  CAS  PubMed  Google Scholar 

  2. Chen, G. Y., Liu, M., Wang, F., Bertin, J. & Nunez, G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol. 186, 7187–7194 (2011)

    Article  CAS  PubMed  Google Scholar 

  3. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl Acad. Sci. USA 108, 9601–9606 (2011)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  5. Centers for Disease Control and Prevention. CDC Estimates of Foodbornes Illness in the United States, 2011 Estimates. http://www.cdc.gov/foodborneburden/2011-foodborne-estimates.html

  6. Scallan, E. et al. Foodborne illness acquired in the United States—major pathogens. Emerg. Infect. Dis. 17, 7–15 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  7. Anand, P. K. et al. TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via ERK activation. J. Biol. Chem. 286, 42981–42991 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Corr, S. C. & O'Neill, L. A. Listeria monocytogenes infection in the face of innate immunity. Cell. Microbiol. 11, 703–709 (2009)

    Article  CAS  PubMed  Google Scholar 

  9. Hybiske, K. & Stephens, R. S. Exit strategies of intracellular pathogens. Nature Rev. Microbiol. 6, 99–110 (2008)

    Article  CAS  Google Scholar 

  10. Creagh, E. M. & O'Neill, L. A. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 27, 352–357 (2006)

    Article  CAS  PubMed  Google Scholar 

  11. Kanneganti, T. D. Central roles of NLRs and inflammasomes in viral infection. Nature Rev. Immunol. 10, 688–698 (2010)

    Article  CAS  Google Scholar 

  12. Pétrilli, V., Dostert, C., Muruve, D. A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007)

    Article  PubMed  Google Scholar 

  13. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  14. Grenier, J. M. et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-κB and caspase-1. FEBS Lett. 530, 73–78 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Stevenson, M. M., Kongshavn, P. A. & Skamene, E. Genetic linkage of resistance to Listeria monocytogenes with macrophage inflammatory responses. J. Immunol. 127, 402–407 (1981)

    CAS  PubMed  Google Scholar 

  16. Lara-Tejero, M. et al. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203, 1407–1412 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006)

    Article  CAS  Google Scholar 

  18. Meixenberger, K. et al. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1β, depending on listeriolysin O and NLRP3. J. Immunol. 184, 922–930 (2010)

    Article  CAS  PubMed  Google Scholar 

  19. Waterfield, M. R., Zhang, M., Norman, L. P. & Sun, S. C. NF-κB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol. Cell 11, 685–694 (2003)

    Article  CAS  PubMed  Google Scholar 

  20. van Ooij, C. Immunology: NLRP6 keeps the bad bacteria at bay. Nature Rev. Microbiol. 9, 481 (2011)

    Article  CAS  Google Scholar 

  21. Girardin, S. E. et al. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science 300, 1584–1587 (2003)

    Article  CAS  ADS  PubMed  Google Scholar 

  22. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005)

    Article  CAS  ADS  PubMed  Google Scholar 

  23. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006)

    Article  CAS  Google Scholar 

  24. Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zaki, M. H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Portnoy, D. A., Jacks, P. S. & Hinrichs, D. J. Role of hemolysin for the intracellular growth of Listeria monocytogenes. J. Exp. Med. 167, 1459–1471 (1988)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Coyle, E. Grant and R. Flavell for the supply of mutant mice. M.L. is supported by grants from the European Union Framework Program 7 (Marie-Curie Grant 256432), European Research Council (grant 281600) and the Fund for Scientific Research Flanders (G030212N, 1.2.201.10.N.00 and 1.5.122.11.N.00). This work was supported by National Institute of Health Grants (AR056296 and AI101935), and the American Lebanese Syrian Associated Charities (ALSAC) to T.-D.K.

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Authors and Affiliations

  1. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Paras K. Anand, R. K. Subbarao Malireddi, John R. Lukens & Thirumala-Devi Kanneganti

  2. Animal Resources Center and the Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, 38105, Tennessee, USA

    Peter Vogel

  3. Pattern Recognition Receptor DPU, Immuno-Inflammation TA, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA,

    John Bertin

  4. Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium,

    Mohamed Lamkanfi

  5. Department of Medical Protein Research, VIB, B-9000 Ghent, Belgium,

    Mohamed Lamkanfi

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  1. Paras K. Anand
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Contributions

T.-D.K., M.L. and P.K.A. designed the research; P.K.A., R.K.S.M. and J.R.L. performed the experiments; P.V. performed and analysed the histopathology data; J.B. provided essential reagents; T.-D.K., M.L., P.K.A., R.K.S.M., J.R.L., P.V. and J.B. analysed the data; P.K.A., M.L. and T.-D.K. wrote the paper; and T.-D.K. conceived the study, designed the experiments and provided overall direction. M.L. and T.-D.K. contributed equally to this work.

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Correspondence to Thirumala-Devi Kanneganti.

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The authors declare no competing financial interests.

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Anand, P., Malireddi, R., Lukens, J. et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488, 389–393 (2012). https://doi.org/10.1038/nature11250

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