Characterization of noncanonical inflammasome-mediated release of alarmins

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

Noncanonical inflammasome sensing of LPS in the cytosol has emerged as a central mechanism of innate immune activation during Gram-negative bacterial infections. While optimal engagement of the cytosolic LPS sensing pathway can be host protective during bacterial infections, its excessive and prolonged activation is highly deleterious and involved in sepsis. A comprehensive understanding of how cytosolic LPS sensing by noncanonical inflammasome contributes to host defense and sepsis is lacking. Innate immune detection of LPS in the cytosol via inflammatory caspases (4,5 and 11) elicits three distinct outcomes; proteolytic maturation of caspase-1, IL-1?, and IL-18, pyroptosis, unconventional secretion of intracellular proteins, which lack leader sequence for secretion via classical endoplasmic reticulum (ER)-Golgi route. Upon extracellular release, several of these proteins are believed to act as alarmins or damage associated molecular patterns (DAMPs), and can both incite and modulate ongoing immune responses. Thus, alarmins and DAMPs play substantial roles in shaping inflammatory responses and tissue repair during infectious diseases, sepsis and trauma. However, the unconventional protein secretion as a consequence of caspase-11 activation by cytosolic LPS is poorly characterized. The overall goal of this study is to profile alarmins released as a consequence of caspase-11 activation by cytosolic LPS. Importantly, we will characterize the secretion and function of a novel alarmin identified in our preliminary studies in regulating innate immune responses during bacterial infections and sepsis. Overall, the findings of this study will provide critical insights into pathogenic mechanisms in sepsis and potentially identify new biomarkers and targets to intervene in sepsis.