Friday, May 9, 2025
5/9/2025
Mechanisms regulating neutrophil proinflammatory activity in sepsis - Sepsis is the leading cause of death in intensive care units and often results in multiorgan failure caused by dysregulated immune responses to infection. There are over 700,000 sepsis cases in the U.S. annually, and approximately 250,000 people die as a result. Despite our understanding of the pathology of sepsis, the treatment options are limited. During sepsis, neutrophils are excessively recruited to the inflamed endothelium in multiple organs and contribute to tissue damage. Furthermore, proinflammatory neutrophils interact with platelets and form microthrombi, exacerbating thrombo-inflammatory conditions. Thus, the goals of this proposal are to understand the molecular mechanisms regulating neutrophil proinflammatory and adhesive activities in sepsis and identify an effective therapeutic strategy for treating the disease. In our latest study, we have demonstrated that neutrophil downstream regulatory element antagonist modulator (DREAM) is a crucial transcriptional repressor that promotes neutrophil recruitment during TNF-α-induced inflammation. Mechanistically, neutrophil DREAM suppresses the expression of A20 (Tnfaip3), an endogenous inhibitor of nuclear factor-κB (NF-κB) signaling and enhances neutrophil proinflammatory and adhesive activities through IκB kinase β (IKKβ) activity. In this project, we will study whether neutrophil A20 signaling contributes to vaso- occlusive events and organ damage in SCD. In this project, we will study whether neutrophil A20 signaling contributes to organ damage in sepsis. In Aim 1, we will determine the molecular basis of neutrophil A20 signaling in regulating neutrophil proinflammatory function under septic conditions. In Aim 2, we will utilize two-photon intravital microscopy to investigate the pathological role of neutrophil A20 signaling in neutrophil recruitment and pulmonary microcirculation in septic mice. In Aim 3, we will determine the contribution of neutrophil A20 signaling to cell-cell aggregation in the blood of septic patients and illness severity. These studies will employ biochemical, cell biological, and intravital imaging approaches. Since little is known about neutrophil A20 signaling in sepsis, the proposed study will identify a novel molecular and cellular mechanism mediating excessive neutrophil recruitment and organ damage in sepsis, which can help design an effective therapeutic strategy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).