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NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens

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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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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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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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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