AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis.

Ruochan Chen,Borong Zhou,Yi Sheng,Ling Zeng,Daolin Tang,Shan Zhu,Rui Kang,Qingde Wang

doi:10.3389/fimmu.2019.01904

Abstract

Inflammasome activation can trigger an inflammatory and innate immune response through the release of cytokines and induction of pyroptosis. A dysfunctional inflammasome has been implicated in the development of human pathologies, including sepsis and septic shock. Here, we show that advanced glycosylation end-product specific receptor (AGER/RAGE) is required for caspase-11 inflammasome activation in macrophages. A nuclear damage-associated molecular pattern (nDAMP) complex, including high-mobility group box 1, histone, and DNA, can promote caspase-11-mediated gasdermin D cleavage, interleukin 1β proteolytic maturation, and lactate dehydrogenase release. The inhibition of AGER-mediated lipid peroxidation via arachidonate 5-lipoxygenase (ALOX5) limits caspase-11 inflammasome activation and pyroptosis in macrophages in response to nDAMPs or cytosolic lipopolysaccharide. Importantly, the pharmacologic inhibition of the AGER-ALOX5 pathway or global depletion (Ager−/−) or conditional depletion of AGER in myeloid cells (AgerMye−/−) protects against lipopolysaccharide-induced septic death in poly(I:C)-primed mice. These data identify a molecular basis for caspase-11 inflammasome activation and provide a potential strategy to treat sepsis.

Highlights

Inflammation is an immune system response to danger signals, including foreign pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs)
The deletion of Casp11 [but not NLR family pyrin domain containing 3 (Nlrp3)] blocked HHD-induced cytotoxicity (Figure 1A), cell viability inhibition (Figure 1B), IL-1β release (Figure 1C), IL-18 release (Figure 1D), and IL-1α release (Figure 1E) in bone-marrowderived macrophages (BMDMs). These findings indicate that caspase-11-dependent non classical inflammasome, but not caspase-1-dependent NLRP3 inflammasome, is an essential mediator of nDAMPinduced pyroptosis
We demonstrated that AGER-mediated lipid peroxidation is critical for caspase11 inflammasome activation in macrophages (Figure 8)

Summary

Introduction

Inflammation is an immune system response to danger signals, including foreign pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). These danger signals are recognized by specific pattern recognition receptors to trigger various immune responses as well as host cell death. The activation of caspase-11 by cytosolic LPS drives the production of mature interleukin (IL)-1 family cytokines (e.g., IL-1β and IL-18), as well as gasdermin D (GSDMD) cleavage, which is responsible for the AGER and Caspase-11 induction of pyroptosis, a form of regulated cell death mainly in macrophages and monocytes [6,7,8,9]. Caspase-11 inflammasome and its modulation have considerable potential as a therapeutic approach in lethal inflammation [11]

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Results

Conclusion