An optimal balance between inflammatory and anti-inflammatory responses is crucial for host defense and impaired responses to invasive pathogens results in bacteremia and septic shock, while an overreaction causes uncontrolled systemic inflammation, which can also lead to shock and multi-organ failure. Sepsis incidence rates are on the rise and it is a significant health problem by causing widespread endothelial and cardiak dysfunction. Lipopolysaccharide (LPS) from Gram negative bacteria causes NLRP3-dependent inflammasome activation in macrophages, which is required for host defense, but can also cause excessive systemic inflammation. In particular the pro-inflammatory cytokine interleukin (IL)-1beta; and the alarmin high mobility group box 1 (HMGB1) are produced by inflammasomes and play a central role mediating the cytokine storm, progressive multi-organ failure and hypotension leading to septic shock and death. Optimal intervention in the excessive host response remains an unmet clinical challenge and thus, elucidating the regulatory mechanisms of inflammasome activation is highly significant for providing novel targets for developing therapies to prevent and treat detrimental systemic inflammation. We discovered the protein POP1 and established the POP family of endogenous inflammasome inhibitors. POP1 is lacking from mice and likely evolved in humans for tighter inflammasome regulation. Therefore, POPs have not been studied in vivo. We generated unique transgenic mice expressing POP1 specifically in macrophages and provide preliminary results that POP1 blocks the Nlrp3 inflammasome in macrophages. The objective of this application is to investigate the potential of POP1 to block the systemic inflammatory hyperresponse and lethal effects caused by pathogen infection, thereby preventing sepsis, and to evaluate recombinant POP1 as a treatment strategy to prevent the systemic cytokine storm. Our two aims are designed to provide a molecular mechanism of POP1-mediated NLRP3 inflammasome inhibition in macrophages and to test POP1 inflammasome inhibition using two established models of sterile and infectious endotoxic shock in vivo. Our rationale for this research is that, once we understand the molecular mechanism by which POP1 regulates inflammasome activation during sepsis, we expect that it will become possible to design POP1-based therapies for septic patients and further to provide the first in vivo data for a POP family member.
|Effective start/end date||7/1/13 → 12/31/15|
- American Heart Association Midwest Affiliate (13GRNT17110117)
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