TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1-IKKβ-IRF5 Signaling Pathway

被引：99

作者：

Bergstrom, Bjarte ^{[1
]}

Aune, Marie H. ^{[1
]}

Awuh, Jane A. ^{[1
]}

Kojen, June F. ^{[1
]}

Blix, Kjetil J. ^{[1
]}

Ryan, Liv ^{[1
]}

Flo, Trude H. ^{[1
]}

Mollnes, Tom E. ^{[1
,2
,3
,4
,5
]}

Espevik, Terje ^{[1
]}

Stenvik, Jorgen ^{[1
]}

机构：

[1] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Ctr Mol Inflammat Res, N-7491 Trondheim, Norway

[2] Oslo Univ Hosp, Rikshosp, Dept Immunol, N-0027 Oslo, Norway

[3] Univ Oslo, KG Jebsen Inflammat Res Ctr, N-0027 Oslo, Norway

[4] Nordland Hosp, Res Lab, N-8092 Bodo, Norway

[5] Univ Tromso, Inst Clin Med, N-9037 Tromso, Norway

来源：

JOURNAL OF IMMUNOLOGY | 2015年 / 195卷 / 03期

关键词：

NF-KAPPA-B; INTERFERON-ALPHA-BETA; IKK-BETA; BORRELIA-BURGDORFERI; HUMAN-LYMPHOCYTES; CELL-ACTIVATION; CUTTING EDGE; RECOGNITION; RECEPTOR; IRF5;

D O I：

10.4049/jimmunol.1403176

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88-NF-kappa B signaling. S. aureus can also induce the production of IFN-beta, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-beta induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-beta production but instead can suppress the induction of IFN-beta in human primary monocytes and monocyte-derived macrophages. The production of IFN-beta was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and I kappa B kinase (IKK)beta, which thus reveals a physiological role of the recently described IRF5-activating function of IKK beta. TLR8-IRF5 signaling was necessary for induction of IFN-beta and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-beta and IL-12 production via a TAK1-IKKb-IRF5 pathway that can be inhibited by TLR2 signaling.

引用

页码：1100 / 1111

页数：12