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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Gene Expression Omnibus
WHO. The world health report 2004—changing history. 121 (WHO, Geneva, 2004).
Mead, P.S. & Griffin, P.M. Escherichia coli O157:H7. Lancet 352, 1207–1212 (1998).
Centers for Disease Control (CDC). Ongoing multistate outbreak of Escherichia coli serotype O157:H7 infections associated with consumption of fresh spinach–United States, September 2006. MMWR Morb. Mortal. Wkly. Rep. 55, 1045–1046 (2006).
Eckmann, L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann. NY Acad. Sci. 1072, 28–38 (2006).
Schauer, D.B. & Falkow, S. Attaching and effacing locus of a Citrobacter freundii biotype that causes transmissible murine colonic hyperplasia. Infect. Immun. 61, 2486–2492 (1993).
MacDonald, T.T. & Monteleone, G. Immunity, inflammation and allergy in the gut. Science 307, 1920–1925 (2005).
Takahashi, A. et al. Production of β-defensin-2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein. FEBS Lett. 508, 484–488 (2001).
Bry, L. & Brenner, M.B. Critical role of T cell–dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J. Immunol. 172, 433–441 (2004).
Maaser, C. et al. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect. Immun. 72, 3315–3324 (2004).
Simmons, C.P. et al. Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-γ. J. Immunol. 168, 1804–1812 (2002).
Goncalves, N.S. et al. Critical role for tumor necrosis factor-α in controlling the number of lumenal pathogenic bacteria and immunopathology in infectious colitis. Infect. Immun. 69, 6651–6659 (2001).
Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004).
Renauld, J-C. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat. Rev. Immunol. 3, 667–676 (2003).
Gurney, A.L. IL-22, a TH1 cytokine that targets the pancreas and select other peripheral tissues. Int. Immunopharmacol. 4, 669–677 (2004).
Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).
Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23–induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
Brand, S. et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G827–G838 (2006).
Levillayer, F., Mas, M., Levi-Acobas, F., Brahic, M. & Bureau, J.F. Interleukin 22 is a candidate gene for Tmevp3, a locus controlling Theiler's virus–induced neurological diseases. Genetics 176, 1835–1844 (2007).
Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).
Misse, D. et al. IL-22 participates in an innate anti–HIV-1 host-resistance network through acute-phase protein induction. J. Immunol. 178, 407–415 (2007).
Weber, G.F. et al. Inhibition of interleukin-22 attenuates bacterial load and organ failure during acute polymicrobial sepsis. Infect. Immun. 75, 1690–1697 (2007).
Wolk, K. et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur. J. Immunol. 36, 1309–1323 (2006).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Nagalakshmi, M.L., Murphy, E., McClanahan, T. & de Waal Malefyt, R. Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization. Int. Immunopharmacol. 4, 577–592 (2004).
Andoh, A. et al. Interleukin-22, a Member of the IL-10 subfamily, Induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129, 969–984 (2005).
Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).
Sa, S.M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).
Happel, K.I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005).
Toy, D. et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006).
Kuestner, R.E. et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J. Immunol. 179, 5462–5473 (2007).
Witowski, J., Ksiazek, K. & Jorres, A. Interleukin-17: a mediator of inflammatory responses. Cell. Mol. Life Sci. 61, 567–579 (2004).
Vallance, B.A., Deng, W., Knodler, L.A. & Finlay, B.B. Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect. Immun. 70, 2070–2081 (2002).
Ganz, T. Defensins and host defense. Science 286, 420–421 (1999).
Cash, H.L., Whitham, C.V., Behrendt, C.L. & Hooper, L.V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).
Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).
Keilbaugh, S.A. et al. Activation of RegIIIβ/γ and interferon γ expression in the intestinal tract of SCID mice: an innate response to bacterial colonisation of the gut. Gut 54, 623–629 (2005).
Ogawa, H. et al. Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm. Bowel Dis. 9, 162–170 (2003).
Ogawa, H., Fukushima, K., Sasaki, I. & Matsuno, S. Identification of genes involved in mucosal defense and inflammation associated with normal enteric bacteria. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G492–G499 (2000).
Iovanna, J., Orelle, B., Keim, V. & Dagorn, J.C. Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J. Biol. Chem. 266, 24664–24669 (1991).
Moucadel, V. et al. Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I. Eur. J. Cell Biol. 80, 156–163 (2001).
Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I. & Stappenbeck, T.S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. USA 102, 99–104 (2005).
Kebir, H. et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 13, 1173–1175 (2007).
Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23–deficient mice. J. Immunol. 172, 2827–2833 (2004).
Camerini, V., Panwala, C. & Kronenberg, M. Regional specialization of the mucosal immune system. Intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine. J. Immunol. 151, 1765–1776 (1993).
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.
All authors are employed by Genentech.
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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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