Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3-primed human monocytes
Monguió Tortajada, Marta (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Franquesa, Marcella (Institut Germans Trias i Pujol)
Sarrias, Maria-Rosa (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Borràs i Serres, Francesc Enric (Institut Germans Trias i Pujol)
Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia

Fecha:	2018
Resumen:	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.
Ayudas:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-804 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002-16-00234 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002-16-00069 Instituto de Salud Carlos III CPII14-00021
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Cell death and disease, Vol. 9 (May 2018) , art. 499, ISSN 2041-4889

DOI: 10.1038/s41419-018-0520-2
PMID: 29717111

14 p, 1.9 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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