Abstract
Sepsis is a life-threating multi-organ disease induced by host innate immunity to pathogen-derived endotoxins including lipopolysaccharide (LPS). Direct sensing of LPS by caspase-11 activates inflammasomes and causes lethal sepsis in mice. Inhibition of caspase-11 inflammasomes is important for the prevention of LPS-induced septic shock; however, whether a caspase-11 inflammasome-specific suppressive mechanism exists is unclear. Here we show that deficiency of GABARAP autophagy-related proteins results in over-activation of caspase-11 inflammasomes but not of canonical inflammasomes. Gate-16−/−Gabarap−/− macrophages exhibited elevated guanylate binding protein 2 (GBP2)-dependent caspase-11 activation and inflammatory responses. Deficiency of GABARAPs resulted in formation of GBP2-containing aggregates that promote IL-1β production. High mortality after low dose LPS challenge in Gate-16−/−Gabarap−/− mice primed with poly(I:C) or polymicrobial sepsis was ameliorated by compound GBP2 deficiency. These results reveal a critical function of Gate-16 and Gabarap to suppress GBP2-dependent caspase-11-induced inflammation and septic shock.
Highlights
Sepsis is defined as a life-threatening multi-organ dysfunction syndrome caused by the excessive induction of host innate immunity against microbial infection [1]
We explored how guanylate binding protein 2 (GBP2) is involved in the hyperactivation of caspase-11 inflammasomes in Gate-16−/−Gabarap−/− macrophages
We demonstrated that deficiency of the GABARAP subfamily proteins such as Gate-16 and Gabarap enhances activation of caspase-11 inflammasome in response to specific LPS stimulation
Summary
Sepsis is defined as a life-threatening multi-organ dysfunction syndrome caused by the excessive induction of host innate immunity against microbial infection [1]. Various microbes contain endotoxins that have critical roles in the induction of sepsis [3]. Lipopolysaccharide (LPS), a cell-wall component of Gram-negative bacteria, is a major endotoxin that strongly stimulates host innate immunity [4]. Extracellular LPS is recognized by cell surface receptor complexes containing Toll-like receptor 4 (TLR4) together with CD14, LPS binding protein (LBP), and Myeloid Differentiation factor 2 (MD-2). Activation of TLR4 signaling cascades mediates the production of proinflammatory cytokines such as TNF-α, IL-6, and IL-12, and precursor (preform) proteins of IL-1β and IL-18 (proIL-1β and proIL-18), which are critical for tissue damage and high fever during sepsis [6]
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