Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens

Abstract

Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIβ and RegIIIγ, in colonic epithelial cells. Exogenous mouse or human RegIIIγ substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.

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Figure 1: Host defense against C. rodentium infection.
Figure 2: IL-22 deficiency renders mice susceptible to C. rodentium infection.
Figure 3: IL-19, IL-20, IL-24 and IL-17 are all dispensable during C. rodentium infection.
Figure 4: Crucial role of IL-22 in early host defense for maintenance of colonic epithelial cell integrity against C. rodentium.
Figure 5: IL-22, produced by DCs, is crucial for innate immune responses against C. rodentium infection.
Figure 6: Reg family proteins mediate important host defense mechanisms downstream of IL-22.

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Acknowledgements

The authors thank A. Chan, H. Spits, E. Brown and B. Irving, all in Genentech, Inc., for critical suggestions; A. Minn and J. Ding, in Genentech, Inc., for the constructs of RegIII fusion proteins; W. Lee, C. Dela Cruz and the Genentech Histology and Immunohistochemistry Laboratories for technical assistance.

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Contributions

Y.Z. performed the majority of the experimental work. P.A.V. characterized IL-20Rβ knockout mice, developed IHC staining for IL-22 and contributed partly to Figures 2, 3, 4, 5 and 6. D.M.D. contributed to the majority of the histological analysis. Y.H. characterized the IL-17RC knockout mice and partly contributed to Figure 3. S.M.S. characterized human colon cell lines. Q.G. partly contributed to Figure 4. Z.M. and A.R.A. performed all of the microarray and bioinformatic analyses, respectively, and contributed partly to Figure 6. N.G. and F.J.d.S. provided and characterized p19 knockout mice and contributed partly to Figure 1. W.O. characterized IL-22R expression on various cells. W.O. and Y.Z. devised and planned the project. The manuscript was written by W.O., Y.Z., D.M.D. and P.A.V.

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Correspondence to Wenjun Ouyang.

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All authors are employed by Genentech.

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Supplementary Figs. 1–7, Supplementary Table 1 and Supplementary Methods (PDF 2267 kb)

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Zheng, Y., Valdez, P., Danilenko, D. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14, 282–289 (2008). https://doi.org/10.1038/nm1720

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