Alarmin(g) outcomes of intracellular LPS sensing

Abstract

Abstract Intracellular sensing of LPS by inflammatory caspases such as caspase-11 has emerged as a key mechanism of innate immune activation during Gram-negative bacterial infections. Cytosolic recognition of LPS by caspase-11 leads to inflammatory cell death or pyroptosis and maturation of IL-1 cytokines. Remarkably, the activation of inflammatory caspases also results in the extracellular release of alarmins and damage associated molecular patterns (DAMPs). These alarmins and DAMPs lack leader signals for classical secretion and are therefore released via a caspase-11 mediated unconventional secretory mechanism. Alarmins and DAMPs—structurally diverse molecules participating in various cellular processes under steady state conditions—are released rapidly upon infections and tissue damage. In the extracellular milieu, these proteins elicit inflammatory reactions by regulating pattern recognition receptor signaling and recruiting innate cells. Despite their potential roles in sepsis, the identity of alarmins and DAMPs released as a result of cytosolic LPS sensing and their contribution to sepsis are poorly understood. Addressing this knowledge gap, we employed an unbiased proteomic approach involving two-dimensional liquid phase fractionation system and mass spectrometry and identified alarmins released in response to caspase-11 activation by cytosolic LPS. In this presentation, the molecular basis of secretion of a candidate alarmin in vitro and in vivo as well as its function in murine models of host defense will be discussed.