Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

被引：21

作者：

Diaz-del-Olmo, Ines ^{[1
]}

Worboys, Jonathan ^{[1
]}

Martin-Sanchez, Fatima ^{[1
]}

Gritsenko, Anna ^{[1
]}

Ambrose, Ashley R. ^{[1
]}

Tannahill, Gillian M. ^{[2
]}

Nichols, Eva-Maria ^{[2
]}

Lopez-Castejon, Gloria ^{[1
]}

Davis, Daniel M. ^{[1
]}

机构：

[1] Univ Manchester, Fac Biol Med & Hlth, Lydia Becker Inst Immunol & Inflammat, Div Infect Immun & Resp Med, Manchester, Lancs, England

[2] GSK, Adapt Immun Res Unit, Stevenage, Herts, England

来源：

FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷

基金：

英国惠康基金;

关键词：

membrane attack complex; inflammasome; macrophage; IL-1; beta; complement; NLRP3; INTERLEUKIN-1; SECRETION; EPITHELIAL-CELLS; C5A RECEPTOR; REMOVAL; SHOCK; ENDOCYTOSIS; NEUTROPHILS; PYROPTOSIS; INHIBITOR; CASPASES;

D O I：

10.3389/fimmu.2021.720655

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Interleukin 1 beta (IL-1 beta) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1 beta release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1 beta release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1 beta release in human macrophages.

引用

页数：14

共 63 条

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