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Sci Immunol. 2018 Aug 3;3(26). pii: eaao4747. doi: 10.1126/sciimmunol.aao4747.

Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma.

Author information

1
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2
Program in Cellular and Molecular Medicine, Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
3
BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, MA 02129, USA.
4
Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA 17033, USA.
5
Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
6
Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, Washington University, St. Louis, MO 63110, USA.
7
Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA.
8
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH 44106, USA.
9
Section of Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, WI 53792, USA.
10
Pulmonary, Allergy, and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
11
Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
12
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. blevy@bwh.harvard.edu.

Abstract

Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis. In addition to neutrophil extracellular traps (NETs), enucleated neutrophil cytoplasts were evident in the lungs. Surprisingly, allergen-driven airway neutrophilia was decreased in peptidyl arginine deiminase 4-deficient mice with defective NETosis but not by deoxyribonuclease treatment, implicating the cytoplasts for the non-type 2 immune responses to allergen. Neutrophil cytoplasts were also present in mediastinal lymph nodes, and the cytoplasts activated lung dendritic cells in vitro to trigger antigen-specific interleukin-17 (IL-17) production from naïve CD4+ T cells. Bronchoalveolar lavage fluid from patients with severe asthma and high neutrophil counts had detectable NETs and cytoplasts that were positively correlated with IL-17 levels. Together, these translational findings have identified neutrophil cytoplast formation in asthmatic lung inflammation and linked the cytoplasts to T helper 17-mediated neutrophilic inflammation in severe asthma.

PMID:
30076281
PMCID:
PMC6320225
[Available on 2019-08-03]
DOI:
10.1126/sciimmunol.aao4747

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