A human-specific long noncoding RNA regulator of antigen-presenting cell viability and antimicrobial defense
Abstract
Macrophages are essential for both, to clear pathogens and preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR (survival associated immune-regulatory RNA), a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in a nuclear factor kappa B (NF-κB) dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis, and invasion factors, which include SIGLEC1 and MMP7. During infection with Salmonella Typhimurium, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the antiapoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator in linking macrophage survival to host–pathogen interaction and disease pathophysiology.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Alexander J. Westermann
Department of Microbiology, Biocenter, University of Würzburg
Alexandra Schock
Institute for Molecular Infection Biology, Faculty of Medicine, University of Würzburg
Diyaa Al Din Ashour
Department of Internal Medicine I, University Hospital Würzburg
Sarah Wende
Institute for Lung Research, Faculty of Medicine, Philipps University Marburg
Chrysanthi Skevaki
Institute of Clinical Chemistry and Laboratory Medicine, and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg-University Mainz
Elisabeth Mack
Department of Hematology, Oncology and Immunology, Philipps University Marburg, University Hospital Giessen and Marburg
Bernd Schmeck
Institute for Lung Research, Faculty of Medicine, Philipps University Marburg
Uwe Linne
Mass spectrometry facility of the Department of Chemistry, Philipps University
Thomas Herrmann
Institute for Virology and Immunobiology, Faculty of Medicine, Julius Maximilians Universität Würzburg
Nikolaos Antonakos
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Helena Florou
Hellenic Institute for the Study of Sepsis
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Sebastian Weis
Institute for Infectious Disease and Infection Control, Jena University Hospital, Friedrich Schiller University
Jörg Vogel
Leon N. Schulte
Institute for Lung Research, Faculty of Medicine, Philipps University Marburg