Journal ArticleDOI
CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation
Ivan Zanoni,Renato Ostuni,Giusy Capuano,Maddalena Collini,Michele Caccia,Antonella Ronchi,Marcella Rocchetti,Francesca Mingozzi,Maria Foti,Giuseppe Chirico,Barbara Costa,Antonio Zaza,Paola Ricciardi-Castagnoli,Paola Ricciardi-Castagnoli,Francesca Granucci +14 more
TLDR
It is shown that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cγ2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT translocation, and LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiateddendritic cells.Abstract:
Toll-like receptors (TLRs) are the best characterized pattern recognition receptors. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor kappaB, activation protein 1 and interferon regulatory factors. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca(2+)/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cgamma2 activation, influx of extracellular Ca(2+) and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.read more
Citations
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Journal ArticleDOI
Innate immune pattern recognition: a cell biological perspective.
TL;DR: This review highlights aspects of cell biology in pattern-recognition receptor signaling by focusing on signals that originate from the cell surface, from endosomal compartments, and from within the cytosol.
Journal ArticleDOI
CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4
Ivan Zanoni,Renato Ostuni,Lorri R. Marek,Simona Barresi,Roman Barbalat,Gregory M. Barton,Francesca Granucci,Jonathan C. Kagan +7 more
TL;DR: It is reported that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4, and this innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction.
Journal ArticleDOI
Single-Cell Transcriptomics of Human and Mouse Lung Cancers Reveals Conserved Myeloid Populations across Individuals and Species.
Rapolas Zilionis,Rapolas Zilionis,Camilla Engblom,Christina Pfirschke,Virginia Savova,David Zemmour,Hatice D. Saatcioglu,Indira Krishnan,Indira Krishnan,Giorgia Maroni,Giorgia Maroni,Giorgia Maroni,Claire V. Meyerovitz,Clara M. Kerwin,Sun Choi,William G. Richards,Assunta De Rienzo,Daniel G. Tenen,Daniel G. Tenen,Raphael Bueno,Elena Levantini,Elena Levantini,Elena Levantini,Mikael J. Pittet,Allon M. Klein +24 more
TL;DR: The lung TIM landscape is determined and sets the stage for future investigations into the potential of TIMs as immunotherapy targets by using single-cell RNA sequencing to map TIMs in non-small-cell lung cancer patients.
Journal ArticleDOI
NFAT, immunity and cancer: a transcription factor comes of age
TL;DR: This Review focuses on recent advances in the understanding of the transcriptional functions of NFAT proteins in the immune system and provides new insights into their potential roles in cancer development.
Journal ArticleDOI
Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling
TL;DR: The current state of the knowledge on the involvement of rafts in TLR4 signaling is summarized, with an emphasis on how the raft proteins regulate the TLR 4 signaling pathways.
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