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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References
Sun, S.C. Deubiquitylation and regulation of the immune response. Nat. Rev. Immunol. 8, 501–511 (2008).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Aderem, A. & Ulevitch, R.J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).
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).
Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nat. Immunol. 3, 221–227 (2002).
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).
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).
Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).
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).
Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692–703 (2009).
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).
Peukert, K. et al. An alternative pathway for gene regulation by Myc. EMBO J. 16, 5672–5686 (1997).
Bardwell, V.J. & Treisman, R. The POZ domain: a conserved protein-protein interaction motif. Genes Dev. 8, 1664–1677 (1994).
Herold, S. et al. Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol. Cell 10, 509–521 (2002).
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).
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).
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).
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).
Ziegelbauer, J. et al. Transcription factor MIZ-1 is regulated via microtubule association. Mol. Cell 8, 339–349 (2001).
Lin, A. Temporal control of TNFα signaling by Miz1. Adv. Exp. Med. Biol. 691, 127–128 (2011).
Budinger, G.R. et al. Proapoptotic Bid is required for pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 103, 4604–4609 (2006).
Gebhardt, A. et al. Miz1 is required for hair follicle structure and hair morphogenesis. J. Cell Sci. 120, 2586–2593 (2007).
Urich, D. et al. Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury. J. Cell Sci. 124, 2927–2937 (2011).
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).
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).
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).
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).
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).
Mason, R.J. Biology of alveolar type II cells. Respirology 11 (suppl.), S12–S15 (2006).
Hoetzenecker, W. et al. ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. Nat. Med. 18, 128–134 (2012).
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).
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).
Marino, M.W. et al. Characterization of tumor necrosis factor-deficient mice. Proc. Natl. Acad. Sci. USA 94, 8093–8098 (1997).
Sultzer, B.M. Genetic control of leucocyte responses to endotoxin. Nature 219, 1253–1254 (1968).
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).
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Adhikary, S. et al. Miz1 is required for early embryonic development during gastrulation. Mol. Cell Biol. 23, 7648–7657 (2003).
Poli, V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J. Biol. Chem. 273, 29279–29282 (1998).
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).
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).
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).
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).
Saccani, S., Pantano, S. & Natoli, G. Two waves of nuclear factor κB recruitment to target promoters. J. Exp. Med. 193, 1351–1359 (2001).
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).
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).
Liu, J. et al. NF-κB is required for UV-induced JNK activation via induction of PKCdelta. Mol. Cell 21, 467–480 (2006).
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).
Urich, D. et al. Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation. FASEB J. 23, 2055–2064 (2009).
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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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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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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DOI: https://doi.org/10.1038/ni.2566
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