Neutrophil extracellular traps impair fungal clearance in a mouse model of invasive pulmonary aspergillosis

Astrid Alflen; Pamela Aranda Lopez; Ann-Kathrin Hartmann; Joachim Maxeiner; Markus Bosmann; Arjun Sharma; Johannes Platten; Frederic Ries; Hendrik Beckert; Wolfram Ruf; Markus P Radsak

doi:10.1016/j.imbio.2019.11.002

Neutrophil extracellular traps impair fungal clearance in a mouse model of invasive pulmonary aspergillosis

Immunobiology. 2020 Jan;225(1):151867. doi: 10.1016/j.imbio.2019.11.002. Epub 2019 Nov 13.

Authors

Affiliations

¹ Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
² Institute for Immunology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
³ Asthma Core Facility, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁴ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, USA.
⁵ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁶ Department of Pulmonary Medicine, University Medical Center Essen - Ruhrlandklinik, Essen, Germany.
⁷ Department of Internal Medicine III, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Electronic address: radsak@uni-mainz.de.

Abstract

Neutrophil extracellular traps (NETs) are formed by polymorphonuclear neutrophils (PMN) and contribute to the innate host defense by binding and killing bacterial and fungal pathogens. Because NET formation depends on histone hypercitrullination by peptidylarginine deiminase 4 (PAD4), we used PAD4 gene deficient (Pad4^-/-) mice in a mouse model of invasive pulmonary aspergillosis (IPA) to address the contribution of NETs to the innate host defense in vivo. After the induction (24 h) of IPA by i.t. infection with Aspergillus fumigatus conidia, Pad4^-/- mice revealed lower fungal burden in the lungs, accompanied by less acute lung injury, TNFα and citH3 compared to wildtype controls. These findings suggest that release of NETs contributes to tissue damage and limits control of fungal outgrowth. Thus inhibition of NETosis might be a useful strategy to maintain neutrophil function and avoid lung damage in patients suffering from IPA, especially in those suffering from preexisting pulmonary disease.

Keywords: Aspergillus fumigatus; Neutrophil extracellular traps; Neutrophils; Peptidylarginine deiminase 4; Pneumonia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Aspergillus fumigatus / physiology*
Citrullination / genetics
Disease Models, Animal
Extracellular Traps / metabolism*
Humans
Immunity, Innate
Invasive Pulmonary Aspergillosis / immunology
Invasive Pulmonary Aspergillosis / metabolism*
Lung / metabolism*
Lung / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils / immunology*
Protein-Arginine Deiminase Type 4 / genetics

Substances

Protein-Arginine Deiminase Type 4
peptidylarginine deiminase 4, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding