Defining marco as an innate checkpoint (F31AI197725) – Project Grant to University Of Massachusetts…

Abstract: Sepsis is a devastating inflammatory condition that develops because of an exaggerated immune response to infection or injury. While sepsis results in nearly 270,000 deaths each year in the united states, no targeted diagnostic tests or treatments have been developed. Recognition of cytosolic bacterial lipopolysaccharide (LPS) plays a key role in initiating septic shock via the activation of innate immune sensors, specifically caspase-11 mediated activation of the non-canonical inflammasome. Inflammasome activation drives pyroptosis, an inflammatory form of cell death, via the cleavage of the pore-forming protein of gasdermin d (gsdmd). While the signaling events that drive LPS recognition and inflammasome activation have been well characterized, IT is not well-understood how the detection of cytosolic LPS is restricted at homeostatic conditions. Our preliminary data indicates that the scavenger receptor macrophage receptor with collagenous structure (marco) binds LPS and can restrict pyroptosis driven by cytosolic LPS. Marco is basally expressed on tissue-resident macrophages and can bind and clear unopsonized particles. Thus, the central hypothesis of this proposal is that marco clears LPS from the extracellular environment to limit intracellular LPS detection and pyroptosis. In support of this hypothesis, we have found that marco expression and LPS clearance are negatively regulated by interferons (ifns). Marco expression on macrophages is dependent on NRF2 and the metabolite itaconate. However, ifns suppress NRF2 stabilization and marco expression. Furthermore, we have found that marco- deficient mice are hypersusceptible to LPS-induced septic shock. Together, this data suggests a model in which ifns suppress marco expression to facilitate maximum LPS detection and pyroptosis. I will test this hypothesis through two distinct aims. In aim 1, i will define the mechanism by which ifns regulate marco expression in macrophages via defining how NRF2 is stabilized in macrophages and identifying the IFN-stimulated gene that restricts NRF2 stabilization. In aim 2, i will identify the role of marco in the activation of the non-canonical inflammasome and the development of sepsis by determining if marco mediates extracellular LPS clearance, defining how marco-deficiency impacts LPS detection, and by determining if marco-deficiency promotes polymicrobial septic shock. Completion of these aims will both define the role and the mechanisms of regulation for a novel LPS decoy receptor. Furthermore, this research will determine how changes to cell metabolism and innate immune signaling impact immune surveillance, macrophage pyroptosis, and pathogenesis of sepsis. In addition to the scientific advances made in this project, i will improve my (1) technical skill set, (2) background knowledge, (3) presentation skills, (4) scientific writing, and (5) professional development through the activities conducted during this fellowship. Together, the work i conduct during this fellowship will support my development into an independent scientist and prepare me to pursue a career in academic research.

Defining marco as an innate checkpoint

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