Over 500,000 people develop sepsis annually in United States alone, resulting in 175,000 fatalities. The complexity of the innate host response and its relevance to determining the ultimate response to pathogens and danger signals is particularly relevant to the sepsis response. Recently, cell injury and apoptosis has been described as key regulator of immune responses in sepsis. Although much is known about the pathogenesis of cell injury and death in sepsis, there are several gaps in our knowledge; as a result of which there is currently no effective pharmacologic therapy. In this context, enzymes known as caspases are essential for completion of the apoptotic program. Phagocytes, in particular monocyte/macrophages, are recognized as major components of inflammatory and immunologic reactions in the lung and are rich reservoirs of caspases, especially caspase-1. The function of caspase-1 has recently been recognized to extend beyond the processing and activation of IL-1 and IL-18 to include regulation of NF-kB and induction of apoptosis. The present proposal seeks to expand upon our recent observation that microvesicular caspase-1 can be released from mononuclear phagocytes to have distant effects on target cells. The present proposal seeks to investigate a novel hypothesis that links the apoptotic enzyme, caspase-1, encapsulated in circulatory vesicles, to cell injury and apoptosis. This proposal provides a much needed effort and framework to study the poorly understood mechanism of splenic and peripheral blood lymphocyte depletion in septic patients, enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the organ destruction in septic patients. Therefore, to determine the specifics of this novel pathway, we propose the following specific aims: 1) To identify the role of caspase-1 in regulating sepsis response via inflammasome activation events., 2) To elucidate the mechanisms by which caspase-1 released from mononuclear phagocyte regulates lymphocyte survival and function in severe sepsis and 3) To determine if caspase-1 mediated lymphocyte loss predicts clinic outcomes in septic patients This proposal provides an opportunity to examine the role of caspase-1 in the complex biology of cell interactions and apoptosis. Successful completion of this work will uncover critical components of microvesicular caspase-1 and inflammasome signaling enhance our understanding of the molecular mechanisms underlying the cell injury and provide new therapeutic opportunities to halt the organ destruction in septic patients.
Over 500,000 people develop sepsis annually in United States alone, resulting in 175,000 fatalities. Recently, cell injury and apoptosis has been described as key regulator of immune responses in sepsis. The severity of injury remains a critical determinant of survival in patients suffering from sepsis. A component of this injury is de to programmed death of cells by poorly understood pathways. This proposal seeks to identify and characterize a novel cell death pathway caused by a packaged delivery of the enzyme caspase-1 in microvesicles. Our study will determine if caspase-1 released in submicroscopic packages may interact with target cells to induce their death. Studies outlined here will study the formation and release, as well as cell uptake of these death packages. We expect this approach to uncover novel insights into organ injury of septic patients and thus create new therapeutic opportunities to prevent and treat patients with sepsis and other inflammatory diseases.
| Mitra, Srabani; Exline, Matthew; Habyarimana, Fabien et al. (2018) Microparticulate Caspase 1 Regulates Gasdermin D and Pulmonary Vascular Endothelial Cell Injury. Am J Respir Cell Mol Biol 59:56-64 |
