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IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia

Nature Medicine volume 14, pages 275–281 (2008)Cite this article

Abstract

Emerging evidence supports the concept that T helper type 17 (TH17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the TH17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony–stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the TH17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.

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Figure 1: Primary HBE cells express IL-22R, and stimulation with IL-22 and IL-17A leads to the upregulation of host defense genes and increases clonogenic frequency.
Figure 2: IL-22 expression is elevated in mice infected with K. pneumoniae, and neutralizing IL-22 leads to decreased bacterial clearance from lung and spleen.
Figure 3: IL-22 and IL-17A regulation of pulmonary cytokines and chemokines in K. pneumoniae infection.
Figure 4: IL-22 production in vivo requires IL-23.
Figure 5: Il23a−/− mice rescued with IL-22, IL-17A and both cytokines have augmented Cxcl1, Cxcl2 and Cxcl9 expression in airways and alveolar epithelium.
Figure 6: IL-22 augments the antimicrobial activity of MTEC cells in vitro.

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Acknowledgements

The authors would like to acknowledge support from the following Public Health Service grants: 5R01HL079142 (J.K.K.), P50HL084932, and P30DK072506 (J.K.K. and J.M.P.). We would like to thank Y. Iwakura (Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo) for the Il17a−/− mice, and T. Mak (University Health Network, Toronto) for the Lcn2−/− mice.

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Authors and Affiliations

  1. Children's Hospital of Pittsburgh, Suite 3765, 3705 Fifth Avenue, Pittsburgh, 15213, Pennsylvania, USA

    Shean J Aujla, Mingquan Zheng, Mingjian Fei, Derek A Pociask, Florencia McAllister, Jennifer Edeal, James L Kreindler, Patricia J Dubin & Jay K Kolls

  2. Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, 3459 Fifth Avenue, 628 Northwest, Pittsburgh, 15213, Pennsylvania, USA

    Yvonne R Chan, Joseph M Pilewski & Mike M Myerburg

  3. University of Pittsburgh Medical Center Newborn Medicine Program, Children's Hospital of Pittsburgh and Magee-Women's Research Institute, 300 Halket Street, Pittsburgh, 15213, Pennsylvania, USA

    David J Askew

  4. Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, 15261, Pennsylvania, USA

    Todd A Reinhart & Kristi Gaus

  5. Division of Infectious Diseases, Transplant Infectious Disease Unit, University of Pittsburgh Medical Center, 3601 Fifth Avenue, Pittsburgh, 15213, Pennsylvania, USA

    Shahid Husain

  6. Division of Pulmonary and Critical Care Medicine, Louisiana Health Sciences Center, New Orleans, 1901 Perdido Street, Louisiana, 70112, USA

    Carol A Mason

  7. Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yoichiro Iwakura

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Contributions

S.J.A. performed all the experiments depicted in Figures 1, 2b,d,e,g,h,3,4,6a–d and g and wrote the manuscript. Y.R.C. performed the experiment depicted in Figure 6f. M.F. and M.Z. performed experiments depicted in Figure 2a,c,f. D.J.A. provided MTECs and assisted in experiments depicted in Figure 6a–c. D.A.P. assisted in experiments depicted in Figures 2g,h and 3. P.J.D. assisted in experiments depicted in Figure 4. F.M. performed experiments depicted in Figure 6e. T.A.R. and K.G. performed in situ hybridization as shown in Figure 5. J.E. performed the experiments with L. monocytogenes (Supplementary Fig. 2). C.A.M. performed the experiments with M. tuberculosis (Supplementary Fig. 1). S.H. provided BAL samples and helpful discussions in experiments depicted in Supplementary Table 1. J.L.K., J.M.P. and M.M.M. supplied HBE cells and helped performed experiments for Figure 1. Y.I. provided Il17A−/− mice, as well as useful discussion in experimental design. J.K.K. was responsible for experimental design, microarray analysis and final manuscript preparation.

Corresponding author

Correspondence to Jay K Kolls.

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Supplementary Figs. 1–6 and Supplementary Table 1 (PDF 165 kb)

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Aujla, S., Chan, Y., Zheng, M. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14, 275–281 (2008). https://doi.org/10.1038/nm1710

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