Mycoplasma pneumoniae lipids license TLR-4 for activation of NLRP3 inflammasome and autophagy to evoke a proinflammatory response.

Abstract:

:Mycoplasma pneumoniae is an obligate pathogen that causes pneumonia, tracheobronchitis, pharyngitis and asthma in humans. It is well recognized that membrane lipoproteins are immunostimulants exerting as lipopolysaccharides (LPS) and play a crucial role in the pathogenesis of inflammatory responses upon M. pneumoniae infection. Here, we report that the M. pneumoniae-derived lipids are another proinflammatory agents. Using an antibody-neutralizing assay, RNA interference or specific inhibitors, we found that Toll-like receptor 4 (TLR-4) is essential for M. pneumoniae lipid-induced tumour necrosis factor (TNF)-α and interleukin (IL)-1β production. We also demonstrate that NLR family pyrin domain containing 3 inflammasome (NLRP3) inflammasome, autophagy and nuclear factor kappa B (NF-κB)-dependent pathways are critical for the secretion of proinflammatory cytokines, while inhibition of TLR-4 significantly abrogates these events. Further characterization revealed that autophagy-mediated inflammatory responses involved the activation of NF-κB. In addition, the activation of NF-κB promoted lipid-induced autophagosome formation, as revealed by assays using pharmacological inhibitors, 3-methyladenine (3-MA) and Bay 11-7082, or silencing of atg5 and beclin-1. These findings suggest that, unlike the response to lipoprotein stimulation, the inflammation in response to M. pneumoniae lipids is mediated by the TLR-4 pathway, which subsequently initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-κB signalling cascade, ultimately promoting TNF-α and Il-1β production in macrophages.

journal_name

Clin Exp Immunol

authors

Luo H,He J,Qin L,Chen Y,Chen L,Li R,Zeng Y,Zhu C,You X,Wu Y

doi

10.1111/cei.13510

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

66-79

issue

1

eissn

0009-9104

issn

1365-2249

journal_volume

203

pub_type

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