Rapamycin Inhibited Pyroptosis and Reduced the Release of IL-1β and IL-18 in the Septic Response.

Luo Zhuo,Xiaobing Chen,Yanli Wang,Wei Xia,Jiayan Han,Yan Sun,Dongmei Chen,Lin Bu,Xiaomin Li,Yuanfeng Shi

doi:10.1155/2020/5960375

Abstract

Pyroptosis, an inflammatory form of programmed cell death, is the initiating event of sepsis and results in immune imbalance by releasing IL-1β and IL-18 in the early stages. Studies show that enhancing autophagy via genetic manipulation can inhibit pyroptosis and prolong the survival of a sepsis animal model, indicating a possible therapeutic strategy against sepsis. However, almost no study so far has achieved pyroptosis inhibition via pharmacological autophagy induction in a sepsis disease model. To this end, we established an in vitro sepsis model by stimulating primary human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and analyzed the effect of the autophagy agonist rapamycin (RAPA) on pyroptosis. Phorbol 12-myristate 13-acetate- (PMA-) activated human THP-1 cells were used as the positive control. LPS significantly increased the levels of the pyroptotic protein Gasdermin D (GSDMD), cysteinyl aspartate-specific proteinase 1 (caspase-1), secreted LDH, IL-1β, and IL-18. RAPA treatment downregulated the above factors and enhanced autophagy in the LPS-stimulated HUVECs and THP-1 cells. This study shows that RAPA abrogates LPS-mediated increase in IL-1β and IL-18 by inhibiting pyroptosis and enhancing autophagy.

Highlights

Pyroptosis is an inflammatory form of programmed cell death that is triggered following infection with intracellular pathogens and may contribute to the innate immune response [1, 2]
human umbilical vein endothelial cells (HUVECs) were cultured with LPS, while human THP-1 cells were induced to differentiate into macrophages, were cultured with LPS
A significant time-dependent increase of IL-18 in supernatant was found in both models (P < 0:05, Figure 2(d) and 3(e)) and IL-1β increased in THP-1 model (P < 0:001, Figure 3(d))

Summary

Introduction

Pyroptosis is an inflammatory form of programmed cell death that is triggered following infection with intracellular pathogens and may contribute to the innate immune response [1, 2]. It begins with the recognition of the pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP) by the pattern recognition receptor (PRR) on the host immune cells, which induces the inflammasome pathway [3]. The latter cleaves caspase-1, which in turn cleaves the downstream caspases (caspase-4/5 in humans and 11 in mice), as well as the prointerleukin-1 beta (IL-β) and IL-18 into their active forms. Sepsis is a potentially fatal medical condition that results from the body’s response to bacterial infection and can lead to multiple organ failure, septic shock, and even death [5, 6]. Since it is usually diagnosed at the later stages, the treatment

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Conclusion