Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis

Florian Gaertner (), Hellen Ishikawa-Ankerhold, Susanne Stutte, Wenwen Fu, Jutta Weitz, Anne Dueck, Bhavishya Nelakuditi, Valeria Fumagalli, Dominic Heuvel, Larissa Belz, Gulnoza Sobirova, Zhe Zhang, Anna Titova, Alejandro Martinez Navarro, Kami Pekayvaz, Michael Lorenz, Louisa Baumgarten, Jan Kranich, Tobias Straub, Bastian Popper, Vanessa Zheden, Walter Anton Kaufmann, Chenglong Guo, Guido Piontek, Saskia Stillfried, Peter Boor, Marco Colonna, Sebastian Clauß, Christian Schulz, Thomas Brocker, Barbara Walzog, Christoph Scheiermann, William C. Aird, Claus Nerlov, Konstantin Stark, Tobias Petzold, Stefan Engelhardt, Michael Sixt, Robert Hauschild, Martina Rudelius, Robert A. J. Oostendorp, Matteo Iannacone, Matthias Heinig and Steffen Massberg
Additional contact information
Florian Gaertner: LMU Munich
Hellen Ishikawa-Ankerhold: LMU Munich
Susanne Stutte: LMU Munich
Wenwen Fu: LMU Munich
Jutta Weitz: LMU Munich
Anne Dueck: Partner site Munich Heart Alliance
Bhavishya Nelakuditi: LMU Munich
Valeria Fumagalli: IRCCS San Raffaele Scientific Institute
Dominic Heuvel: LMU Munich
Larissa Belz: LMU Munich
Gulnoza Sobirova: LMU Munich
Zhe Zhang: LMU Munich
Anna Titova: LMU Munich
Alejandro Martinez Navarro: LMU Munich
Kami Pekayvaz: LMU Munich
Michael Lorenz: LMU Munich
Louisa Baumgarten: Ludwig-Maximilians-University School of Medicine
Jan Kranich: LMU Munich
Tobias Straub: LMU Munich
Bastian Popper: LMU Munich
Vanessa Zheden: Institute of Science and Technology Austria (ISTA)
Walter Anton Kaufmann: Institute of Science and Technology Austria (ISTA)
Chenglong Guo: LMU Munich
Guido Piontek: Ludwig-Maximilians-University Munich
Saskia Stillfried: RWTH Aachen University Hospital
Peter Boor: RWTH Aachen University Hospital
Marco Colonna: School of Medicine
Sebastian Clauß: LMU Munich
Christian Schulz: LMU Munich
Thomas Brocker: LMU Munich
Barbara Walzog: LMU Munich
Christoph Scheiermann: LMU Munich
William C. Aird: Beth Israel Deaconess Medical Center
Claus Nerlov: University of Oxford, John Radcliffe Hospital
Konstantin Stark: LMU Munich
Tobias Petzold: LMU Munich
Stefan Engelhardt: Partner site Munich Heart Alliance
Michael Sixt: Institute of Science and Technology Austria (ISTA)
Robert Hauschild: Institute of Science and Technology Austria (ISTA)
Martina Rudelius: Ludwig-Maximilians-University Munich
Robert A. J. Oostendorp: Technical University of Munich
Matteo Iannacone: IRCCS San Raffaele Scientific Institute
Matthias Heinig: Partner site Munich Heart Alliance
Steffen Massberg: LMU Munich

Nature, 2024, vol. 631, issue 8021, 645-653

Abstract: Abstract Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.

Date: 2024
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DOI: 10.1038/s41586-024-07671-y

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