Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ

Abstract

Transcription factor NF-κB and its activating kinase IKKβ are associated with inflammation and are believed to be critical for innate immunity. Despite the likelihood of immune suppression, pharmacological blockade of IKKβ–NF-κB has been considered as a therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKKβ (IkkβΔ mice). These mice had hyperproliferative granulocyte-macrophage progenitors and pregranulocytes and a prolonged lifespan of mature neutrophils that correlated with the induction of genes encoding prosurvival molecules. Deletion of interleukin 1 receptor 1 (IL-1R1) in IkkβΔ mice normalized blood cellularity and prevented neutrophil-driven inflammation. However, IkkβΔIl1r1−/− mice, unlike IkkβΔ mice, were highly susceptible to bacterial infection, which indicated that signaling via IKKβ–NF-κB or IL-1R1 can maintain antimicrobial defenses in each other's absence, whereas inactivation of both pathways severely compromises innate immunity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: IkkβΔ mice develop neutrophilia.
Figure 2: Neutrophilia in IKKβ-deficient mice is transplantable.
Figure 3: Ablation of IL-1R1 prevents neutrophilia in IkkβΔ mice.
Figure 4: Larger granulocyte progenitor populations in IkkβΔ mice.
Figure 5: Effects of IKKβ ablation on neutrophil lifespan and gene expression.
Figure 6: Inactivation of signaling via IL-1–IL-1R1 and IKKβ–NF-κB compromises antimicrobial immunity.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Segal, A.W. How neutrophils kill microbes. Annu. Rev. Immunol. 23, 197–223 (2005).

    Article  CAS  Google Scholar 

  2. Klebanoff, S.J. & Clark, R.A. The Neutrophil: Function and Clinical Disorders 5–162 (Elsevier/North-Holland, Amsterdam, 1978).

  3. Quie, P.G. The phagocytic system in host defense. Scand. J. Infect. Dis. Suppl 24, 30–32 (1980).

    CAS  Google Scholar 

  4. Burg, N.D. & Pillinger, M.H. The neutrophil: function and regulation in innate and humoral immunity. Clin. Immunol. 99, 7–17 (2001).

    Article  CAS  Google Scholar 

  5. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  Google Scholar 

  6. von Kockritz-Blickwede, M. & Nizet, V. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps. J. Mol. Med. 87, 775–783 (2009).

    Article  Google Scholar 

  7. Lundqvist-Gustafsson, H. & Bengtsson, T. Activation of the granule pool of the NADPH oxidase accelerates apoptosis in human neutrophils. J. Leukoc. Biol. 65, 196–204 (1999).

    Article  CAS  Google Scholar 

  8. Nathan, C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173–182 (2006).

    Article  CAS  Google Scholar 

  9. Metcalf, D. Stem cells, pre-progenitor cells and lineage-committed cells: are our dogmas correct? Ann. NY Acad. Sci. 872, 289–303 (1999).

    Article  CAS  Google Scholar 

  10. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  Google Scholar 

  11. Yang, L. et al. Identification of LinSca1+kit+CD34+Flt3 short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood 105, 2717–2723 (2005).

    Article  CAS  Google Scholar 

  12. Metcalf, D. & Nicola, N.A. The Hemopoietic Colony Stimulating Factors 109–165 (Cambridge University Press, Cambridge, UK, 1995).

  13. Barnes, P.J. & Karin, M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    Article  CAS  Google Scholar 

  14. Greten, F.R. & Karin, M. The IKK/NF-κB activation pathway-a target for prevention and treatment of cancer. Cancer Lett. 206, 193–199 (2004).

    Article  CAS  Google Scholar 

  15. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  16. Bonizzi, G. & Karin, M. The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25, 280–288 (2004).

    Article  CAS  Google Scholar 

  17. Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13 (2006).

    Article  Google Scholar 

  18. Straus, D.S. Design of small molecules targeting transcriptional activation by NF-κB: overview of recent advances. Expert Opin. Drug Discov. 4, 823–836 (2009).

    Article  CAS  Google Scholar 

  19. Baud, V. & Karin, M. Is NF-κB a good target for cancer therapy? Hopes and pitfalls. Nat. Rev. Drug Discov. 8, 33–40 (2009).

    Article  CAS  Google Scholar 

  20. Nagashima, K. et al. Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKβ. Blood 107, 4266–4273 (2006).

    Article  CAS  Google Scholar 

  21. Greten, F.R. et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007).

    Article  CAS  Google Scholar 

  22. Mbalaviele, G. et al. A novel, highly selective, tight binding IκB kinase-2 (IKK-2) inhibitor: a tool to correlate IKK-2 activity to the fate and functions of the components of the nuclear factor-κB pathway in arthritis-relevant cells and animal models. J. Pharmacol. Exp. Ther. 329, 14–25 (2009).

    Article  CAS  Google Scholar 

  23. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    Article  CAS  Google Scholar 

  24. Ruocco, M.G. et al. IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J. Exp. Med. 201, 1677–1687 (2005).

    Article  CAS  Google Scholar 

  25. Hestdal, K. et al. Characterization and regulation of RB6–8C5 antigen expression on murine bone marrow cells. J. Immunol. 147, 22–28 (1991).

    CAS  PubMed  Google Scholar 

  26. Dinarello, C.A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

    Article  CAS  Google Scholar 

  27. Vitale, C. et al. Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc. Natl. Acad. Sci. USA 96, 15091–15096 (1999).

    Article  CAS  Google Scholar 

  28. Chen, C., Edelstein, L.C. & Gelinas, C. The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-xL . Mol. Cell. Biol. 20, 2687–2695 (2000).

    Article  Google Scholar 

  29. Boise, L.H. et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).

    Article  CAS  Google Scholar 

  30. Fu, L. et al. Constitutive NF-κB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107, 4540–4548 (2006).

    Article  CAS  Google Scholar 

  31. Resnitzky, D., Hengst, L. & Reed, S.I. Cyclin A-associated kinase activity is rate limiting for entrance into S phase and is negatively regulated in G1 by p27Kip1. Mol. Cell. Biol. 15, 4347–4352 (1995).

    Article  CAS  Google Scholar 

  32. Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).

    Article  CAS  Google Scholar 

  33. He, G. et al. Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297 (2010).

    Article  CAS  Google Scholar 

  34. Horwitz, B.H., Scott, M.L., Cherry, S.R., Bronson, R.T. & Baltimore, D. Failure of lymphopoiesis after adoptive transfer of NF-κB-deficient fetal liver cells. Immunity 6, 765–772 (1997).

    Article  CAS  Google Scholar 

  35. Grossmann, M. et al. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl. Acad. Sci. USA 96, 11848–11853 (1999).

    Article  CAS  Google Scholar 

  36. Senftleben, U., Li, Z.W., Baud, V. & Karin, M. IKKβ is essential for protecting T cells from TNFα-induced apoptosis. Immunity 14, 217–230 (2001).

    Article  CAS  Google Scholar 

  37. Stanley, E.R., Bartocci, A., Patinkin, D., Rosendaal, M. & Bradley, T.R. Regulation of very primitive, multipotent, hemopoietic cells by hemopoietin-1. Cell 45, 667–674 (1986).

    Article  CAS  Google Scholar 

  38. Ueda, Y., Cain, D.W., Kuraoka, M., Kondo, M. & Kelsoe, G. IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia. J. Immunol. 182, 6477–6484 (2009).

    Article  CAS  Google Scholar 

  39. Greten, F.R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  Google Scholar 

  40. Lane, A.A. & Ley, T.J. Neutrophil elastase is important for PML-retinoic acid receptor α activities in early myeloid cells. Mol. Cell. Biol. 25, 23–33 (2005).

    Article  CAS  Google Scholar 

  41. Jamieson, C.H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).

    Article  CAS  Google Scholar 

  42. Genovese, M.C. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

    Article  CAS  Google Scholar 

  43. Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 β converting enzyme. Science 267, 2000–2003 (1995).

    Article  CAS  Google Scholar 

  44. Hsu, L.C. et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc. Natl. Acad. Sci. USA 105, 7803–7808 (2008).

    Article  CAS  Google Scholar 

  45. Temkin, V., Huang, Q., Liu, H., Osada, H. & Pope, R.M. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol. Cell. Biol. 26, 2215–2225 (2006).

    Article  CAS  Google Scholar 

  46. Kranich, J. et al. Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. J. Exp. Med. 205, 1293–1302 (2008).

    Article  CAS  Google Scholar 

  47. Abrahamsson, A.E. et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc. Natl. Acad. Sci. USA 106, 3925–3929 (2009).

    Article  CAS  Google Scholar 

  48. Breckpot, K. et al. Lentivirally transduced dendritic cells as a tool for cancer immunotherapy. J. Gene Med. 5, 654–667 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Kaushansky, G. Wulf and N. Zatula for advice and support; L. Jerabek and A. Mosley for laboratory and animal management; C. Richter and N. Teja for antibody production; and the National Clinical Trial & Research Center at National Taiwan University Hospital, and the Bioinformatics and Biostatistics Core, Research Center for Medical Excellence at National Taiwan University, Taiwan, for microarray services and assistance in data analysis. Supported by the US National Institutes of Health (AI043477 to M.K., AI77780 to V.N. and U01HL099999-02 to I.L.W.), National Taiwan University (L.-C.H.), National Health Research Institutes, Taiwan (NHRI-EX99-9825SC to L.-C.H.)., Leukemia and Lymphoma Society of America (T.E.), California Institute for Regenerative Medicine (J.S.) and American Cancer Society (M.K. and I.L.W.).

Author information

Authors and Affiliations

Authors

Contributions

J.S. and A.M.T. contributed equally to this work. L.-C.H. and T.E. designed and did most of the experiments; M.K. helped in designing experiments; M.K., T.E. and L.-C.H. wrote the paper; J.S. and I.L.W. planned and did most of the progenitor cell analyses; A.M.T. and V.N. planned and did the bacterial killing experiments; and C.-Y.L., T.-Y.L., G.-Y.Y., L.-C.L., V.T., U.S. and T.A. helped with some of the experiments.

Corresponding authors

Correspondence to Li-Chung Hsu or Michael Karin.

Ethics declarations

Competing interests

M.K. holds several US and international patents on the development and use of IKKβ inhibitors; I.L.W. has stock in Amgen, is a cofounder of Cellerant and Stem Cells and is also a consultant for Stem Cells.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Table 1 and Supplementary Methods (PDF 2682 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsu, LC., Enzler, T., Seita, J. et al. IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ. Nat Immunol 12, 144–150 (2011). https://doi.org/10.1038/ni.1976

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1976

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing