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

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

doi:10.1038/s41419-018-0520-2

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.

Highlights

Monocytes, as key actors of the innate immunity, are equipped with a wide range of pathogen recognition receptors (PRRs) to initiate host defence responses against invading pathogens
Our results show that the sequential stimulation of TLR3 and TLR4 leads to the exacerbation of the inflammatory response of monocytes together with the triggering of cell death, which is directly dependent on TLR4 signalling but independent from TNFα
Monocytes were cultured for 24 h in non-stimulated conditions or stimulated with Toll-like receptors (TLRs) agonists LPS (TLR4, 100 ng/ml), poly(I:C) (TLR3, 50 μg/ml) or R848 (TLR7/8, 2.5 μM)

Summary

Introduction

As key actors of the innate immunity, are equipped with a wide range of pathogen recognition receptors (PRRs) to initiate host defence responses against invading pathogens. Among PRRs, specific Toll-like receptors (TLRs) located in the cell membrane and endosomal compartments sense different components of microorganisms known as pathogen-associated molecular patterns[1]. Continuous TLR4 activation with repeated exposure to bacterial LPS, such as in sepsis, promotes hyporesponsiveness of monocytes to subsequent LPS challenge, a phenomenon termed endotoxin tolerance[5,6,7]. Previous studies have shown that different TLR agonists interplay to modulate the inflammatory response to each other[4,8,9,10], synergizing to enhance the immune response or promoting heterotolerance to restrain inflammation instead. Understanding the interactions between TLR signalling that lead to synergy, priming and tolerance to TLR agonists may help explain monocyte plasticity and how prior infections and inflammatory conditioning can modulate the innate immune response to secondary infections or co-infections

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Conclusion