HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes

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dc.contributor.author Moreno-Gonzalo, Olga
dc.contributor.author Ramírez-Huesca, Marta
dc.contributor.author Blas-Rus, Noelia
dc.contributor.author Cibrián, Danay
dc.contributor.author Saiz, María Laura
dc.contributor.author Jorge, Inmaculada
dc.contributor.author Camafeita, Emilio
dc.contributor.author Vázquez, Jesús
dc.contributor.author Sánchez-Madrid, Francisco
dc.contributor.other UAM. Departamento de Medicina Preventiva y Salud Pública y Microbiología es_ES
dc.contributor.other Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-IP) es_ES
dc.date.accessioned 2018-02-13T14:30:06Z
dc.date.available 2018-02-13T14:30:06Z
dc.date.issued 2017-12-27
dc.identifier.citation PLoS Pathogens 13.12 (2017): e1006799 en_US
dc.identifier.issn 1553-7366 (print) es_ES
dc.identifier.issn 1553-7374 (online) es_ES
dc.identifier.uri http://hdl.handle.net/10486/681175
dc.description.abstract Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6 -/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6 +/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection. Hdac6 -/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6 +/+ counterparts, Hdac6 -/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-κB induction after TLR stimuli. Moreover, Hdac6 -/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6 -/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection. en_US
dc.description.sponsorship This study was supported by the following grants to FSM: SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness, INDISNET-S2011/ BMD-2332 from the Comunidad de Madrid, CIBER CARDIOVASCULAR and grant PIE13/00041 from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional; FEDER), and ERC-2011-AdG Desarrollo Regional; FEDER), and ERC-2011-AdG 294340- GENTRIS and COST-Action BM1202 from the European Comission. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). OMG was supported by the fellowship FPU programme was supported by the fellowship FPU programme supported by the fellowship FPI programme (Spanish Ministry of Economy). en_US
dc.format.extent 32 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher Public Library of Science en_US
dc.relation.ispartof PLoS Pathogens en_US
dc.rights © 2017 Moreno-Gonzalo et al. es_ES
dc.subject.other HDAC6 en_US
dc.subject.other Listeria monocytogenes en_US
dc.subject.other Dendritic cells en_US
dc.subject.other Pro-inflammatory cytokines en_US
dc.subject.other Intracellular bacterial infection en_US
dc.title HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion https://doi.org/10.1371/journal.ppat.1006799 es_ES
dc.identifier.doi 10.1371/journal.ppat.1006799 es_ES
dc.identifier.publicationfirstpage e1006799-1 es_ES
dc.identifier.publicationissue 12 es_ES
dc.identifier.publicationlastpage e1006799-32 es_ES
dc.identifier.publicationvolume 13 es_ES
dc.relation.projectID Gobierno de España. SAF2014-55579-R es_ES
dc.relation.projectID Comunidad de Madrid. S2011/ BMD-2332/INDISNET es_ES
dc.relation.projectID Gobierno de España. PIE13/00041 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/294340 es_ES
dc.relation.projectID Gobierno de España. SEV-2015-0505 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento es_ES
dc.rights.accessRights openAccess en
dc.authorUAM Sánchez Madrid, Francisco (259404)


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