Browsing by MeSH term "Myeloid Differentiation Factor 88"
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Publication HDAC6 controls innate immune and autophagy responses to TLR-mediated signalling by the intracellular bacteria Listeria monocytogenes(2017) Moreno-Gonzalo, Olga; Ramirez-Huesca, Marta; Blas-Rus, Noelia; Cibrián, Danay; Saiz, Maria Laura; Jorge, Inmaculada; Camafeita, Emilio; Vazquez, Jesus; Sanchez-Madrid, Francisco; Ministerio de Economía y Competitividad (España); Comunidad de Madrid (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Educación y Ciencia (España); Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Fundación ProCNICRecent 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. 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.Publication Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice(Nature Publishing Group, 2023-08-24) Isidro-Hernández, Marta; Casado-García, Ana; Oak, Ninad; Alemán-Arteaga, Silvia; Ruiz-Corzo, Belén; Martínez-Cano, Jorge; Mayado, Andrea; Sánchez, Elena G; Blanco, Oscar; Gaspar, Maria Luisa; Orfao, Alberto; Alonso-López, Diego; De Las Rivas, Javier; Riesco, Susana; Prieto-Matos, Pablo; González-Murillo, África; García-Criado, Francisco Javier; García-Cenador, María Begoña; Ramírez-Orellana, Manuel; Andres, Belen de; Vicente-Dueñas, Carolina; Cobaleda, César; Nichols, Kim E; Sánchez-García, Isidro; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Fundación Ramón Areces; Banco Santander; Instituto de Salud Carlos III; American Lebanese Syrian Associated Charities; National Cancer Research Institute; Junta de Castilla y León (España); Fundación Unoentrecienmil; Asociación Española Contra el CáncerThe initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5+/- B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5+/-Myd88+/- mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5+/- mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.Publication Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs(Nature Publishing Group, 2015-10) Phinney, Donald G; Di Giuseppe, Michelangelo; Njah, Joel; Sala, Ernest; Shiva, Sruti; St Croix, Claudette M; Stolz, Donna B; Watkins, Simon C; Di, Y. Peter; Leikauf, George D; Kolls, Jay; Riches, David WH; Deiuliis, Giuseppe; Kaminski, Naftali; Boregowda, Siddaraju V; McKenna, David H; Ortiz, Luis AMesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.