Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma.
Nandini KrishnamoorthyDavid N DoudaThayse R BrüggemannIsabell RicklefsMelody G DuvallRaja-Elie E AbdulnourKimberly MartinodLuciana TavaresXiao WangManuela CernadasElliot IsraelDavid T MaugerEugene R BleeckerMario CastroSerpil C ErzurumBenjamin M GastonNizar N JarjourSally E WentzelEleanor M DunicanJohn V FahyDaniel IrimaDenisa D WagnerBruce David Levynull nullPublished in: Science immunology (2019)
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.
Keyphrases
- oxidative stress
- dendritic cells
- immune response
- allergic rhinitis
- lymph node
- end stage renal disease
- chronic kidney disease
- chronic obstructive pulmonary disease
- ejection fraction
- nitric oxide
- lung function
- type diabetes
- toll like receptor
- prognostic factors
- metabolic syndrome
- early stage
- inflammatory response
- replacement therapy
- amino acid