Coraline Radermecker

Infection with SARS-CoV-2 is causing a deadly and pandemic disease called coronavirus disease-19 (COVID-19). While SARS-CoV-2-triggered hyperinflammatory tissue-damaging and immunothrombotic responses are thought to be major causes of respiratory failure and death, how they relate to lung immunopathological changes remains unclear. Neutrophil extracellular traps (NETs) can contribute to inflammation-associated lung damage, thrombosis, and fibrosis. However, whether NETs infiltrate particular compartments in severe COVID-19 lungs remains to be clarified. Here we analyzed postmortem lung specimens from four patients who succumbed to COVID-19 and four patients who died from a COVID-19-unrelated cause. We report the presence of NETs in the lungs of each COVID-19 patient. NETs were found in the airway compartment and neutrophil-rich inflammatory areas of the interstitium, while NET-prone primed neutrophils were present in arteriolar microthrombi. Our results support the hypothesis that NETs may represent drivers of severe pulmonary complications of COVID-19 and suggest that NET-targeting approaches could be considered for the treatment of uncontrolled tissue-damaging and thrombotic responses in COVID-19.

Abstract Resident tissue macrophages (RTM) can fulfill various tasks during development, homeostasis, inflammation and repair. In the lung, non-alveolar RTM, called interstitial macrophages (IM), importantly contribute to tissue homeostasis but remain little characterized. Here we show, using single-cell RNA-sequencing (scRNA-seq), two phenotypically distinct subpopulations of long-lived monocyte-derived IM, i.e. CD206 + and CD206 − IM, as well as a discrete population of extravasating CD64 + CD16.2 + monocytes. CD206 + IM are peribronchial self-maintaining RTM that constitutively produce high levels of chemokines and immunosuppressive cytokines. Conversely, CD206 − IM preferentially populate the alveolar interstitium and exhibit features of antigen-presenting cells. In addition, our data support that CD64 + CD16.2 + monocytes arise from intravascular Ly-6C lo patrolling monocytes that enter the tissue at steady-state to become putative precursors of CD206 − IM. This study expands our knowledge about the complexity of lung IM and reveals an ontogenic pathway for one IM subset, an important step for elaborating future macrophage-targeted therapies.