PhD Candidate UMass Chan Med. Sch. Worcester, Massachusetts, United States
Introduction/Rationale: Cytosolic sensing of bacterial lipopolysaccharide (LPS) is mediated by caspase-11 (caspase-4/5 in humans), which triggers non-canonical inflammasome activation. This leads to gasdermin D cleavage, pyroptosis, and release of pro-inflammatory cytokines. Severe gram-negative bacterial infections cause endotoxic septic shock, with systemic inflammation, organ failure, and potential death. Bacterial derived LPS gains access to the cytosol through extracellular vesicles and CD14 receptor mediated endocytosis. However, how this process is controlled during infection to maintain homeostasis is unknown.
Methods: We performed an unbiased proteomic screen with biotinylated LPS and identified MARCO as an LPS-binding protein by mass spectrometry. Using macrophages from transgenic mice, we defined the mechanism by which MARCO facilitates LPS clearance to limit activation of the non-canonical inflammasome.
Results: MARCO is a scavenger receptor expressed on tissue resident macrophages (TRMs) and is known to promote clearance of pathogens and apoptotic debris. However, there is a lack of genetic studies and a paucity in our understanding of the functional role MARCO plays in innate immunity and how MARCO expression is regulated on TRMs. Here, we show that activation of the non-canonical inflammasome is preceded by a priming step by which type I interferon (IFN) suppresses MARCO expression on TRMs to allow for optimal recognition of LPS and activation of caspase-11. Remarkably, the metabolite itaconate and transcription factor NRF2 mediate MARCO expression. IFN signaling inhibits NRF2 stabilization, reducing surface MARCO levels. In vivo, MARCO-deficient mice show increased sensitivity to LPS-induced septic shock due to enhanced caspase-11 and non-canonical inflammasome activation.
Conclusion: IFN-mediated suppression of MARCO expression is a previously unknown innate checkpoint that facilitates the recognition of LPS by caspase-11, activation of the non-canonical inflammasome, and progression of septic shock.
