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Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ

Nature Immunology volume 14, pages 461–469 (2013)Cite this article

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Abstract

Inflammation is essential for host defense but can cause tissue damage and organ failure if unchecked. How the inflammation is resolved remains elusive. Here we report that the transcription factor Miz1 was required for terminating lipopolysaccharide (LPS)-induced inflammation. Genetic disruption of the Miz1 POZ domain, which is essential for the transactivation or repression activity of Miz1, resulted in hyperinflammation, lung injury and greater mortality in LPS-treated mice but a lower bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged the expression of proinflammatory cytokines. After stimulation, Miz1 was phosphorylated at Ser178, which was required for recruitment of the histone deacetylase HDAC1 to repress transcription of the gene encoding C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying the resolution of LPS-induced inflammation.

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Figure 1: Mice with lung-specific disruption of the Miz1 POZ domain are highly susceptible to LPS-induced inflammation and acute lung injury.
Figure 2: Loss of the Miz1 POZ domain augments the production of proinflammatory cytokines and chemokines in vivo and in vitro.
Figure 3: Loss of the Miz1 POZ domain enhances the production of inflammatory cytokines and chemokines, promotes bacterial clearance and improves the survival of mice with P. aeruginosa pneumonia.
Figure 4: Loss of the Miz1 POZ domain results in upregulation of Cebpd transcription in vivo and in vitro.
Figure 5: Silencing of C/EBP-δ expression abrogates the effect of loss of the Miz1 POZ domain on the production of proinflammatory cytokines and chemokines.
Figure 6: Miz1 recruits HDAC1 to the promoter of Cebpd to repress Cebpd transcription.
Figure 7: TNF-induced recruitment of RelA and ATF-3 to the Cebpd promoter is altered by loss of the Miz1 POZ domain.
Figure 8: Phosphorylation of Miz1 at Ser178 is required for its suppression of Cebpd transcription.

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References

  1. Sun, S.C. Deubiquitylation and regulation of the immune response. Nat. Rev. Immunol. 8, 501–511 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Aderem, A. & Ulevitch, R.J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Hsu, H., Shu, H.B., Pan, M.G. & Goeddel, D.V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299–308 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nat. Immunol. 3, 221–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Liu, J., Minemoto, Y. & Lin, A. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor α-induced c-Jun kinase activation and apoptosis. Mol. Cell Biol. 24, 10844–10856 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu, J. & Lin, A. Wiring the cell signaling circuitry by the NF-κB and JNK1 crosstalk and its applications in human diseases. Oncogene 26, 3267–3278 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Litvak, V. et al. Function of C/EBP-δ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nat. Immunol. 10, 437–443 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Wanzel, M. et al. Akt and 14–3-3ɛ regulate Miz1 to control cell-cycle arrest after DNA damage. Nat. Cell Biol. 7, 30–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Peukert, K. et al. An alternative pathway for gene regulation by Myc. EMBO J. 16, 5672–5686 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bardwell, V.J. & Treisman, R. The POZ domain: a conserved protein-protein interaction motif. Genes Dev. 8, 1664–1677 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Herold, S. et al. Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol. Cell 10, 509–521 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Kosan, C. et al. Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation. Immunity 33, 917–928 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Liu, J. et al. Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α-induced JNK activation and inflammation. Proc. Natl. Acad. Sci. USA 109, 191–196 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, J., Zhao, Y., Eilers, M. & Lin, A. Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-α-induced JNK1 activation. Proc. Natl. Acad. Sci. USA 106, 18279–18284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang, Y. et al. E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFalpha-induced JNK activation. Proc. Natl. Acad. Sci. USA 107, 13444–13449 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ziegelbauer, J. et al. Transcription factor MIZ-1 is regulated via microtubule association. Mol. Cell 8, 339–349 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Lin, A. Temporal control of TNFα signaling by Miz1. Adv. Exp. Med. Biol. 691, 127–128 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Budinger, G.R. et al. Proapoptotic Bid is required for pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 103, 4604–4609 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gebhardt, A. et al. Miz1 is required for hair follicle structure and hair morphogenesis. J. Cell Sci. 120, 2586–2593 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Urich, D. et al. Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury. J. Cell Sci. 124, 2927–2937 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cohen, C.J. et al. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc. Natl. Acad. Sci. USA 98, 15191–15196 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaner, R.J. et al. Modification of the genetic program of human alveolar macrophages by adenovirus vectors in vitro is feasible but inefficient, limited in part by the low level of expression of the coxsackie/adenovirus receptor. Am. J. Respir. Cell Mol. Biol. 20, 361–370 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Mutlu, G.M. et al. Electroporation-mediated gene transfer of the Na+,K+-ATPase rescues endotoxin-induced lung injury. Am. J. Respir. Crit. Care Med. 176, 582–590 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sutherland, K.D. et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell 19, 754–764 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Mason, R.J. Biology of alveolar type II cells. Respirology 11 (suppl.), S12–S15 (2006).

    Article  PubMed  Google Scholar 

  30. Hoetzenecker, W. et al. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nat. Med. 18, 128–134 (2012).

    Article  CAS  Google Scholar 

  31. Labbé, K., McIntire, C.R., Doiron, K., Leblanc, P.M. & Saleh, M. Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome. Immunity 35, 897–907 (2011).

    Article  PubMed  CAS  Google Scholar 

  32. Echtenacher, B., Mannel, D.N. & Hultner, L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 381, 75–77 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Marino, M.W. et al. Characterization of tumor necrosis factor-deficient mice. Proc. Natl. Acad. Sci. USA 94, 8093–8098 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sultzer, B.M. Genetic control of leucocyte responses to endotoxin. Nature 219, 1253–1254 (1968).

    Article  CAS  PubMed  Google Scholar 

  35. O'Brien, A.D. et al. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J. Immunol. 124, 20–24 (1980).

    CAS  PubMed  Google Scholar 

  36. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Adhikary, S. et al. Miz1 is required for early embryonic development during gastrulation. Mol. Cell Biol. 23, 7648–7657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Poli, V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J. Biol. Chem. 273, 29279–29282 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Varlakhanova, N., Cotterman, R., Bradnam, K., Korf, I. & Knoepfler, P.S. Myc and Miz-1 have coordinate genomic functions including targeting Hox genes in human embryonic stem cells. Epigenetics Chromatin 4, 20 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Si, J., Yu, X., Zhang, Y. & DeWille, J.W. Myc interacts with Max and Miz1 to repress C/EBPδ promoter activity and gene expression. Mol. Cancer 9, 92 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Iraci, N. et al. A SP1/MIZ1/MYCN repression complex recruits HDAC1 at the TRKA and p75NTR promoters and affects neuroblastoma malignancy by inhibiting the cell response to NGF. Cancer Res. 71, 404–412 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Zhong, H., May, M.J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Saccani, S., Pantano, S. & Natoli, G. Two waves of nuclear factor κB recruitment to target promoters. J. Exp. Med. 193, 1351–1359 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kung, V.L. et al. An rhs gene of Pseudomonas aeruginosa encodes a virulence protein that activates the inflammasome. Proc. Natl. Acad. Sci. USA 109, 1275–1280 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Beck, J.M. et al. Critical roles of inflammation and apoptosis in improved survival in a model of hyperoxia-induced acute lung injury in Pneumocystis murina-infected mice. Infect. Immun. 77, 1053–1060 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, J. et al. NF-κB is required for UV-induced JNK activation via induction of PKCdelta. Mol. Cell 21, 467–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Zarbock, A. et al. Improved survival and reduced vascular permeability by eliminating or blocking 12/15-lipoxygenase in mouse models of acute lung injury (ALI). J. Immunol. 183, 4715–4722 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Urich, D. et al. Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation. FASEB J. 23, 2055–2064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Hauser, K. Gates, A. Gonzalez and F. Aguilar for help with animal experiments; J. Radder for isolating ATII cells; L. He for isolating lung cells derived from the hematopoietic compartment; A. Yemelyanov for lentivirus preparation; and J. Dewille (Ohio State University College of Veterinary Medicine) for the Cebpd luciferase reporter gene construct. Supported by the US National Institutes of Health (GM081603 to J.L., GM095313 to A.L., ES015024 to G.M.M., ES013995 to G.R.S.B., P01HL071643 to J.I.S., and AI 089954 and AI 091962 to L.Z.).

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Author notes

  1. Hanh Chi Do-Umehara and Cong Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    Hanh Chi Do-Umehara, Cong Chen, Daniela Urich, Samuel Jang, Alia Zander, Margaret A Baker, Peter H S Sporn, Karen M Ridge, Jacob I Sznajder, G R Scott Budinger, Gökhan M Mutlu & Jing Liu

  2. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    Liang Zhou & Ju Qiu

  3. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    Liang Zhou & Ju Qiu

  4. Institute of Molecular Biology and Tumour Research, Philipps University Marburg, Universität Marburg, Marburg, Germany

    Martin Eilers

  5. Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA

    Peter H S Sporn, Karen M Ridge & G R Scott Budinger

  6. Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA

    Anning Lin

  7. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

    Anning Lin

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Contributions

H.C.D.-U. and C.C. did experiments and analyzed the data; D.U., J.Q., S.J. and A.Z. did experiments; M.A.B. isolated ATII cells; M.E., L.Z., P.H.S.S., K.M.R., J.I.S. and A.L. provided reagents; G.R.S.B. and G.M.M. did animal experiments and provided reagents; and J.L. designed and supervised the study, did experiments and wrote the manuscript.

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Correspondence to Jing Liu.

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Do-Umehara, H., Chen, C., Urich, D. et al. Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ. Nat Immunol 14, 461–469 (2013). https://doi.org/10.1038/ni.2566

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