Inhibitory Effect and Mechanism of Arctium lappa Extract on NLRP3 Inflammasome Activation.

Young-Kyu Kim,Myong-Ki Kim,Su-Bin Kwak,Do-Wan Shim,Eun-Jung In,Sang-Hyeun Yu,Kwang-Ho Lee,Tae-Bong Kang,Sushruta Koppula

doi:10.1155/2018/6346734

Abstract

Arctium lappa (A. lappa), Compositae, is considered a potential source of nutrition and is used as a traditional medicine in East Asian countries for centuries. Although several studies have shown its biological activities as an anti-inflammatory agent, there have been no reports on A. lappa with regard to regulatory role in inflammasome activation. The purpose of this study was to investigate the inhibitory effects of A. lappa extract (ALE) on NLRP3 inflammasome activation and explore the underlying mechanisms. We found that ALE inhibited IL-1β secretion from NLRP3 inflammasome activated bone marrow derived macrophages but not that secreted by NLRC4 and AIM2 inflammasomes activation. Mechanistic studies revealed that ALE suppressed the ATPase activity of purified NLRP3 and reduced mitochondrial reactive oxygen species (mROS) generated during NLRP3 activation. Therefore, the inhibitory effect of ALE on NLRP3 inflammasome might be attributed to its ability to inhibit the NLRP3 ATPase function and attenuated the mROS during inflammasome activation. In addition, ALE significantly reduced the LPS-induced increase of plasma IL-1β in mouse peritonitis model. These results provide evidence of novel anti-inflammatory mechanisms of A. lappa, which might be used for therapeutic applications in the treatment of NLRP3 inflammasome-associated inflammatory disorders.

Highlights

IntroductionInflammasomes are cytosolic multimeric protein complexes composed of nucleotide-binding domain and leucinerich-repeat-containing proteins (NLRs) such as NLRP3, NLRC4, or AIM2 (absent in melanoma 2), adapter protein ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1 [1]
Inflammasomes are cytosolic multimeric protein complexes composed of nucleotide-binding domain and leucinerich-repeat-containing proteins (NLRs) such as NLRP3, NLRC4, or AIM2, adapter protein ASC, and caspase-1 [1]
To determine whether A. lappa extract (ALE) has an inhibitory effect on inflammasome activation, LPS-primed Bone marrow derived macrophages (BMDMs) were pretreated with ALE at nontoxic concentrations (Figure 1(a)) before stimulation with NLRP3 agonists, ATP, nigericin, and silica crystals

Summary

Introduction

Inflammasomes are cytosolic multimeric protein complexes composed of nucleotide-binding domain and leucinerich-repeat-containing proteins (NLRs) such as NLRP3, NLRC4, or AIM2 (absent in melanoma 2), adapter protein ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1 [1]. NLRP3 is currently the well-characterized inflammasome and it is activated in response to various stimuli such as extracellular ATP, the potassium ionophore nigericin, and particulates such as silica crystals and asbestos [3,4,5]. The NLRP3 inflammasome is triggered by abnormal metabolites such as cholesterol crystals, monosodium urate crystals, and β-amyloid, which are implicated in the development of various metabolic disorders [6,7,8]. The involvement of NLRP3 inflammasome in various diseases makes it a highly desirable therapeutic target

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