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NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense

Nature Immunology volume 13, pages 449–456 (2012)Cite this article

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Abstract

Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1β (pro-IL-1β). After infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produced mature IL-1β through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1β by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine.

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Figure 1: High expression of pro-IL-1β by iMPs and hyporesponsiveness of iMPs to TLR stimulation.
Figure 2: Salmonella infection induces caspase-1 activation and IL-1β production in iMPs.
Figure 3: Pathogenic bacteria induce activation of the NLRC4 inflammasome in iMPs, but commensal bacteria do not.
Figure 4: Intestinal phagocytes express a functional NLRC4, but not NLRP3, inflammasome.
Figure 5: Nlrc4−/− mice are more susceptible to orogastric Salmonella infection but not to intraperitoneal Salmonella infection.
Figure 6: Il1r1−/− mice are more susceptible to orogastric Salmonella infection but not to intraperitoneal Salmonella infection.
Figure 7: The NLRC4 inflammasome promotes host defense through neutrophil recruitment in the intestine.

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Acknowledgements

We thank H.L. Rosenzweig (Oregon Health & Science University) for Il1r1−/− BALB/c mice; P. Vandenabeele (Ghent University) for purified caspase-1; G.Y. Chen for critically reading the manuscript; and the University of Michigan Flow Cytometry Core, Immune Monitoring Core and Tissue Procurement Service for assistance. Supported by the US National Institutes of Health (R01 DK61707 to G.N.; T32-HL007517 to M.H.S.; and T32 HD007505 to A.B.), the University of Michigan Comprehensive Cancer Center (5 P30 CA46592), the Crohn's and Colitis Foundation of America (L.F. and N.K.) and the Tissue Core of the University of Michigan Comprehensive Cancer Center (CA46952).

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  1. Luigi Franchi and Nobuhiko Kamada: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Luigi Franchi, Nobuhiko Kamada, Yuumi Nakamura, Aaron Burberry, Peter Kuffa, Shiho Suzuki, Michael H Shaw, Yun-Gi Kim & Gabriel Núñez

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Contributions

L.F., N.K. and G.N. conceived of the study; L.F. and N.K. designed and did most of the experiments; P.K. produced antibodies; S.S. and A.B. helped with experiments; P.K., S.S., A.B., M.H.S., Y.N. and Y.-G.K. helped design several experiments and provided advice; G.N. supervised all aspects of the study; and L.F. and G.N. wrote the manuscript with contributions from all authors.

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Correspondence to Gabriel Núñez.

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Franchi, L., Kamada, N., Nakamura, Y. et al. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nat Immunol 13, 449–456 (2012). https://doi.org/10.1038/ni.2263

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