低剂量LPS可加剧炎症反应

Cell Death and Disease

5/2/18Article

5.965

影响因子

原标题:低剂量的LPS加剧炎症反应并触发TLR3引发的人单核细胞死亡

① 使用TLR4激动剂LPS、TLR3激动剂poly(I:C)和TLR7/8激动剂R8484刺激人血单核细胞,随后进行低剂量的内毒素刺激;② 单核细胞中,不同TLR激动剂触发不同的炎症反应特征;③ 使用内毒素后,LPS和R848活化的单核细胞不增强先前的应答,poly(I:C)活化的单核细胞有显著的炎症反应,伴随着细胞活力降低;④ TLR3活化的单核细胞在低内毒素水平下凋亡,同时产生高水平的TNFα和IL6;⑤ 先后刺激TLR3与TLR4,依赖于TLR4信号促进凋亡,而不依赖TNFα。

炎症反应 Toll样受体(TLR)

图片

Title:
Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes

DOI:
10.1038/s41419-018-0520-2

Abstract & Authors展开

Abstract:
TLR sensing of pathogens triggers monocyte activation to initiate the host innate immune response to infection. Monocytes can dynamically adapt to different TLR agonists inducing different patterns of inflammatory response, and the sequence of exposure to TLRs can dramatically modulate cell activation. Understanding the interactions between TLR signalling that lead to synergy, priming and tolerance to TLR agonists may help explain how prior infections and inflammatory conditioning can regulate the innate immune response to subsequent infections. Our goal was to investigate the role of MyD88-independent/dependent TLR priming on modulating the monocyte response to LPS exposure. We stimulated human blood monocytes with agonists for TLR4 (LPS), TLR3 (poly(I:C)) and TLR7/8 (R848) and subsequently challenged them to low doses of endotoxin. The different TLR agonists promoted distinct inflammatory signatures in monocytes. Upon subsequent LPS challenge, LPS- and R848-primed monocytes did not enhance the previous response, whereas poly(I:C)-primed monocytes exhibited a significant inflammatory response concomitant with a sharp reduction on cell viability. Our results show that TLR3-primed monocytes are prompted to cell death by apoptosis in the presence of low endotoxin levels, concurrent with the production of high levels of TNFα and IL6. Of note, blocking of TNFR I/II in those monocytes did reduce TNFα production but did not abrogate cell death. Instead, direct signalling through TLR4 was responsible of such effect. Collectively, our study provides new insights on the effects of cross-priming and synergism between TLR3 and TLR4, identifying the selective induction of apoptosis as a strategy for TLR-mediated host innate response.

All Authors:
Marta Monguió-Tortajada,Marcella Franquesa,Maria-Rosa Sarrias,Francesc E Borràs

First Authors:
Marta Monguió-Tortajada

Correspondence:
Francesc E Borràs

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