当前位置： SCI文献检索 > CRITICAL CARE MEDICINE期刊下所有文献 > Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1β Production, and the Host Immune Response to Infection.

Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1β Production, and the Host Immune Response to Infection.

Abstract：

OBJECTIVES:Monocytes and macrophages produce interleukin-1β by inflammasome activation which involves adenosine triphosphate release, pannexin-1 channels, and P2X7 receptors. However, interleukin-1β can also be produced in an inflammasome-independent fashion. Here we studied if this mechanism also involves adenosine triphosphate signaling and how it contributes to inflammasome activation. DESIGN:In vitro studies with human cells and randomized animal experiments. SETTING:Preclinical academic research laboratory. SUBJECTS:Wild-type C57BL/6 and pannexin-1 knockout mice, healthy human subjects for cell isolation. INTERVENTIONS:Human monocytes and U937 macrophages were treated with different inhibitors to study how purinergic signaling contributes to toll-like receptor-induced cell activation and interleukin-1β production. Wild-type and pannexin-1 knockout mice were subjected to cecal ligation and puncture to study the role of purinergic signaling in interleukin-1β production and host immune defense. MEASUREMENTS AND MAIN RESULTS:Toll-like receptor agonists triggered mitochondrial adenosine triphosphate production and adenosine triphosphate release within seconds. Inhibition of mitochondria, adenosine triphosphate release, or P2 receptors blocked p38 mitogen-activated protein kinase and caspase-1 activation and interleukin-1β secretion. Mice lacking pannexin-1 failed to activate monocytes, to produce interleukin-1β, and to effectively clear bacteria following cecal ligation and puncture. CONCLUSIONS:Purinergic signaling has two separate roles in monocyte/macrophage activation, namely to facilitate the initial detection of danger signals via toll-like receptors and subsequently to regulate nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 inflammasome activation. Further dissection of these mechanisms may reveal novel therapeutic targets for immunomodulation in critical care patients.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Lee AH,Ledderose C,Li X,Slubowski CJ,Sueyoshi K,Staudenmaier L,Bao Y,Zhang J,Junger WG

doi

10.1097/CCM.0000000000003446

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

e1183-e1189

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1β Production, and the Host Immune Response to Infection.