Lentinan from shiitake selectively attenuates AIM2 and non-canonical inflammasome activation while inducing pro-inflammatory cytokine production

Huijeong Ahn,Pyeung-Hyeun Kim,Sung-Il Yoon,Hyun-Jeong Ko,Geun-Shik Lee,Eunsaem Jeon,Seung Goo Kang,Jin-Chul Kim

doi:10.1038/s41598-017-01462-4

Huijeong Ahn, Pyeung-Hyeun Kim + Show 6 more

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https://doi.org/10.1038/s41598-017-01462-4

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Abstract

Lentinan extracted from shiitake (Lentinula edodes) is a β-glucan that has been reported as an intravenous anti-tumor polysaccharide via enhancement of the host immune system. In this study, we determined the effect of lentinan on inflammasome activation, a multi-protein platform, in myeloid cells. Mouse bone marrow-derived macrophages were treated with lentinan with/without inflammasome triggers, and maturation of interleukin (IL)-1β, IL-18, or caspase-1 was measured as a readout of inflammasome activation. As a result, lentinan selectively inhibited absent in melanoma 2 (AIM2) inflammasome activation. In addition, lentinan up-regulated pro-inflammatory cytokines and induced expression of inflammasome-related genes through toll-like receptor 4 signaling. Furthermore, we assessed the effect of lentinan on mice treated with Listeria monocytogenes or lipopolysaccharide as an AIM2 or non-canonical inflammasome-mediated model. Lentinan attenuated IL-1β secretion resulting from Listeria-mediated AIM2 inflammasome activation and reduced endotoxin lethality via inhibition of non-canonical inflammasome activation. Thus, lentinan is suggested as an anti-AIM2 and anti-non-canonical inflammasome candidate despite its up-regulation of cytokine expression.

Highlights

Β-glucans, which have a long history as non-specific immunomodulators, are heterogeneous polysaccharides of glucose polymers1, 2. β-glucans can enhance the functional activity of macrophages as well as the antimicrobial activities of neutrophils and mononuclear cells[3]
To investigate whether or not lentinan alone can activate inflammasomes resulting in IL-1β maturation and secretion, we treated LPS-primed bone marrow-derived macrophages (BMDMs) with increasing dosages of lentinan or ATP, a NLRP3 inflammasome trigger, as a positive control
We investigated whether or not β-glucan originating from different sources can regulate inflammasome activation and gene expression. β-D-Glucan extracted from barley (GB) has a structure consisting of β-(1,3)-glucose units (Supplementary Fig. 1A)

Summary

Introduction

Β-glucans, which have a long history as non-specific immunomodulators, are heterogeneous polysaccharides of glucose polymers1, 2. β-glucans can enhance the functional activity of macrophages as well as the antimicrobial activities of neutrophils and mononuclear cells[3]. Β-glucans can enhance the functional activity of macrophages as well as the antimicrobial activities of neutrophils and mononuclear cells[3]. Inflammasomes, multi-protein complexes, in myeloid cells recognize intracellular pathogen-associated molecular patterns. (PAMPs) and/or danger-associated molecular patterns (DAMPs), leading to activation of caspase-1 followed by maturation of pro-inflammatory cytokines and interleukins (IL)-1β and -1810, 11. The non-canonical inflammasome mediates pyroptosis, endotoxemia, and Escherichia coli-induced septic shock as well as triggers NLRP3 inflammasome activation for maturation of IL-1β and -1813, 14. Inflammasomes, an intracellular surveillant that triggers the inflammatory response, has been suggested as a therapeutic target for cancer treatment[11]. We assessed the role of lentinan in canonical (NLRP3, NLRC4, and AIM2) inflammasome activation and inflammasome-mediated gene expression. We further confirmed the effect of lentinan on non-canonical inflammasome activation

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