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.

Bronchi are exposed daily to irritants, microbes and allergens as well as extremes of temperature and acid. The airway mucosal epithelium plays a pivotal role as a sentinel, releasing alarmins when danger is encountered. To maintain homeostasis, an elaborate counter-regulatory network of signals and cellular effector mechanisms are needed. Specialized pro-resolving mediators (SPMs) are chemical mediators that enact resolution programs in response to injury, infection or allergy. SPMs are enzymatically derived from essential polyunsaturated fatty acids with potent cell-type specific immunoresolvent properties. SPMs signal by engaging cell-based receptors to turn off acute inflammatory responses and restore tissue homeostasis. Several common lung diseases involving the airways, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are characterized by unresolved bronchial inflammation. In preclinical murine models of lung disease, SPMs carry potent bronchoprotective actions. Here, we review cellular and molecular effects for SPM-initiated catabasis in the lung and their human translation.