A redox-sensitive switch in the macrophage nucleus regulates acute phase inflammatory injury

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SUMMARY This application is based on the discovery that reactive oxygen and nitrogen species (RONS) within the nucleus of macrophages are powerful signals regulating the polarization of the early immune response and, in particular, the activation of the acute phase of inflammation. Specifically, we found that the promoters of a subset of pro-inflammatory NFκB-target genes, while remaining constitutively accessible, are muted by association with SOCS1, a redox sensitive protein that binds and depletes incoming p65 NFκB. This mechanism simultaneously prevents inflammatory tissue injury during homeostasis as well as provides a rapid and specific pathway to mobilizing aggressive innate immune cells to hunt and kill highly proliferative pathogenic microbes. NOS1-derived nitric oxide (NO) displaces SOCS1 by S-nitrosylation licensing the transcription of acute pro-inflammatory NFκB-target genes. Because H2O2 (ROS) can modify cysteines similarly to NO, we hypothesize that oxidative stress in the nucleus mimics NO, displacing SOCS1 from regulatory regions of pro-inflammatory genes as well as preventing its de novo deposition thereby extending the acute phase of inflammation and preventing the transition to inflammatory resolution and tissue healing. Clinically, this exacerbates pulmonary tissue injury and elevates the risk of ARDS in patients with underlying oxidative stress caused by old age, smoking, autoimmunity, or other conditions. Interestingly, we found that although suppressing nuclear NO or ROS eliminates much of the inflammatory tissue injury in response to LPS, the ability of mice to control K. pneumoniae infection remains intact, indicating that targeting nuclear NO and ROS with existing compounds may be clinically useful to prevent at-risk patients from evolving to ARDS. Currently, ARDS prevention and management is accomplished by the use of powerful immunosuppressive drugs that compromise the ability of the patient to fight infection. In this regard, this proposed project has the potential to advance a long sought goal in the field that is finding ways to suppress inflammatory tissue injury and ARDS while preserving the ability of innate immune cells to eliminate infectious agents intact.