The current project is focused on the study of basic mechanisms of polarization of the innate immune response. Macrophages are the primary cell type responsible for the polarization of the innate immunity either by initiating and propagating inflammation (M1 phenotype) or resolving inflammation to promote tissue healing (M2 phenotype). A relative new idea is that the dysregulation of macrophage polarization with the prevalence of M1 over M2 phenotype promotes wide-spread inflammation and acute tissue injury. In the case of lungs acute lung injury (ALI) may evolve to acute respiratory distress syndrome (ARDS), a highly lethal form of respiratory failure. Hence, understanding the mechanisms by which macrophages polarize into functionally distinct phenotypes may lead to new therapeutic strategies to prevent or treat ARDS. Nuclear factor ?B (NF?B) is a master regulator of inflammation being responsible for the expression of genes that promote or resolve inflammation. While the p65/p50 configuration of NF?B promotes inflammation, the p50/p50 configuration promotes resolution. We reason that these configurations also regulate how macrophages polarize into distinct phenotypes. In this regard, we recently discovered that suppressor of cytokine signaling-1 (SOCS1) may operate the switch in NF?B function since it targets nuclear p65 but not p50 to degradation changing the relative abundances of these component subunits in the nucleus. The finding that SOCS1 is sensitive to inhibition by nitric oxide (NO) and possibly other reactive species also indicate novel molecular mechanisms by which SOCS1 activity, NF?B function, pro- and anti-inflammatory transcription, as well as macrophage polarization and inflammatory outcomes are regulated. These mechanisms are the focus of our three proposed aims: (1) to determine the mechanism by which SOCS1 promotes NF?B functional switch from that of a pro- to that of an anti-inflammatory transcriptional complex; (2) to determine if changes in the intracellular redox state of macrophages affects SOCS1 activity and NF?B function as a transcription factor and (3) Determine how SOCS1 expression in different immune cell types regulates the transition between inflammation propagation and resolution in a mouse model of bacterial pneumonia.

Public Health Relevance

This project is based on the discovery of a fundamental biochemical process that determines innate immune polarization towards pro- and anti-inflammation leading to inflammatory tissue injury or healing. We recently discovered that suppressor of cytokine signaling-1 (SOCS1), which is a negative regulator of the master inflammatory nuclear factor NF?B, is inhibited by NO produced in the nucleus of macrophages by neuronal nitric oxide synthase (NOS1). This discovery suggests that there is a previously unreported mechanism that determines macrophage function, that impacts inflammation propagation and resolution and that can be potentially targeted to promote pathogen clearance or suppress tissue injury caused by exacerbated inflammation. This application will (1) Determine how the NOS1/SOCS1 axis switches NF?B activity from pro- to anti-inflammatory; (2) How hypoxia and reactive oxygen species, which occur in inflamed tissues, impact this switch; (3) How the NOS1/SOCS1 axis coordinate the mounting of an effective pathogen killing response in the lung that evolves to inflammation resolution and tissue healing. We expect that information generated by these studies will help to develop strategies to inhibit inflammatory lung injury or accelerate inflammatory resolution.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Vazquez-Maldonado, Nancy
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Medical College of Wisconsin
Internal Medicine/Medicine
Schools of Medicine
United States
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