Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Ananda S Mirchandani*, Stephen J Jenkins, Calum C Bain, Manuel Alejandro Sanchez Garcia, Hannah Lawson, Patricia Coelho, Fiona Murphy, David Griffith, Ailiang Zhang, Tyler Morrison, Tony Ly, Simone Arienti, Pranvera Sadiku, Emily R Watts, Rebecca Dickinson, Leila Reyes, George Cooper, Sarah Clark, David Lewis, Van KellyChristos Spanos, Kathryn M Musgrave, Liam Delaney, Isla Harper, Jonathan Scott, Nicholas J Parkinson, Anthony J Rostron, J Kenneth Baillie, Sara Clohisey, Clare Pridans, Lara Campana, Philip Starkey Lewis, A John Simpson, David H Dockrell, Jürgen Schwarze, Nik Hirani, Peter J Ratcliffe, Christopher W Pugh, Kamil Kranc, Stuart J Forbes, Moira K B Whyte, Sarah R Walmsley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. Here we showed that ARDS patients were hypoxemic and monocytopenic within the first 48 hours of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signalling in the bone marrow. This impaired monopoiesis, resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of CSF1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.
Original languageEnglish
JournalNature Immunology
DOIs
Publication statusPublished - 27 May 2022

Fingerprint

Dive into the research topics of 'Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation'. Together they form a unique fingerprint.

Cite this