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.
Original language | English (US) |
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Pages (from-to) | 461-469 |
Number of pages | 9 |
Journal | Nature Immunology |
Volume | 14 |
Issue number | 5 |
DOIs | |
State | Published - May 2013 |
Funding
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.).
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology