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

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 its transactivation or repression activity, resulted in hyper-inflammation, lung injury and increased mortality in LPS-treated mice while reduced bacterial load and mortality in mice with Pseudomonas aeruginosa pneumonia. Loss of the Miz1 POZ domain prolonged pro-inflammatory cytokine expression. Upon stimulation, Miz1 was phosphorylated at Ser178, which is required for recruiting histone deacetylase 1 to repress transcription of C/EBP-δ, an amplifier of inflammation. Our data provide a long-sought mechanism underlying resolution of LPS-induced inflammation.