Dehydroepiandrosterone exacerbates nigericin-induced abnormal autophagy and pyroptosis via GPER activation in LPS-primed macrophages

Abstract

As a widely acknowledged FDA-approved dietary supplement or over-the-counter medicines, dehydroepiandrosterone (DHEA) exerts anti-inflammatory and immunomodulatory function. Pyroptosis is an important form of programmed cell death (PCD), and which acts a key role in the body’s anti-infection and inflammatory responses. But the effects and mechanisms of DHEA on pyroptosis remain unclear. Here, we found that DHEA inhibited the NLRP3 inflammasome components expression by blocking inflammatory signals in lipopolysaccharide (LPS)-primed macrophages, and prevented the bacterial toxin nigericin (Nig)-induced NLRP3 inflammasome assembly. However, DHEA exacerbated NLRP3-independent cell death in Nig-treated inflammatory macrophages. During this process, DHEA induced the abnormal autophagy, which reflected as the blocking of autophagic flux and the accumulation of autophagy receptor p62 (SQSTM1) protein. In addition, DHEA caused a burst of reactive oxygen species (ROS) and activated extracellular signal-regulated kinase (ERK) phosphorylation in LPS plus Nig-stimulated macrophages but not in LPS-treated macrophages. Mechanistically, the present study certified that the activation of G protein-coupled estrogen receptor (GPER) signal mediated the cell death induced by DHEA in Nig-stimulated inflammatory macrophages, as GPER specific inhibitor G15 alleviated the abnormal autophagy and ultimately prevented the gasdermin D (GSDMD)-mediated pyroptosis induced by DHEA. Collectively, DHEA can exacerbate Nig-induced abnormal autophagy and pyroptosis via activation of GPER in LPS-primed macrophages, which prompts us the potential application value of DHEA in anti-infection or anti-tumor immunity.

Platelet-Rich Fibrin Reduces IL-1β Release from Macrophages Undergoing Pyroptosis

“…While ATP is related to the strong increase in the IL-1β release in the LPS-primed macrophages [ 18 , 32 ], other compounds were indicated to play important roles in the pyroptosis pathway, such as α-hemolysin [ 37 , 38 , 39 ] and nigericin [ 40 , 41 ], either alone or in combination with other pathogen-associated molecular patterns (PAMPs). Alpha-hemolysin is a bacterial pore-forming toxin produced by Staphylococcus , which activates inflammasome activity and caspase-1, thus inducing pyroptosis [ 38 , 42 ].…”

“…Nigericin is a microbial toxin produced by Streptomyces hygroscopicus that decreases intracellular potassium, which causes caspase-1 activation and induces the release of IL-1β, leading to pyroptosis [ 30 , 43 ]. Studies on macrophages have been trying to find molecules to reduce pyroptosis in LPS-primed ATP/α-hemolysin/nigericin-stimulated cells [ 41 ] or even exacerbate pyroptosis cell death due to the potential application in anti-infection or anti-tumour immunity [ 40 ]. Nevertheless, this topic is relatively new in periodontal research.…”

NLRP3 inflammasome in digestive diseases: From mechanism to therapy

“…Dehydroepiandrosterone is a vital cholesterol metabolic intermediate and shows protection against DSS-induced colitis both in vivo and in vitro ( 174 ). Notably, a recent study reported that Dehydroepiandrosterone induced autophagy via G protein-coupled estrogen receptorgper (GPER) activation and inhibited NF-κB signaling pathway, leading to decreasing the expression of NLRP3 inflammasome components ( 228 ).…”

Echinacea Polyphenols Inhibit NLRP3-Dependent Pyroptosis, Apoptosis, and Necroptosis via Suppressing NO Production during Lipopolysaccharide-Induced Acute Lung Injury

“…7,8 Once NLRP3 is activated, ASC and pro-caspase-1 would be initiated, leading to caspase-1 activation, and then pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) are processed into their active forms. 9,10 At the same time, gasdermin D (GSDMD) is cleaved to form gasdermin D N-terminal (GSDMD-NT), which migrates to the cell membrane to form the pores, resulting in the release of cell contents and activation of a profound inflammatory response (pyroptosis). Notably, the excessive release of inflammatory cytokines caused by NLRP3-dependent pyroptosis further amplifies the inflammatory reaction during ALI, aggravating tissue damage and functional abnormalities.…”

“…The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. NLRP3 inflammasome plays a decisive role in pathogen infection, autoinflammatory reaction, neurodegenerative diseases, and many other diseases. , Once NLRP3 is activated, ASC and pro-caspase-1 would be initiated, leading to caspase-1 activation, and then pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) are processed into their active forms. , At the same time, gasdermin D (GSDMD) is cleaved to form gasdermin D N-terminal (GSDMD-NT), which migrates to the cell membrane to form the pores, resulting in the release of cell contents and activation of a profound inflammatory response (pyroptosis). Notably, the excessive release of inflammatory cytokines caused by NLRP3-dependent pyroptosis further amplifies the inflammatory reaction during ALI, aggravating tissue damage and functional abnormalities .…”