Single‐cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma

Abstract

Severe equine asthma (SEA) is a complex respiratory condition characterized by chronic airway inflammation. It shares many clinical and pathological features with human neutrophilic asthma, making it a valuable model for studying this condition. However, the immune mechanisms driving SEA have remained elusive. Although SEA has been primarily associated with a Th2 response, there have also been reports of Th1, Th17, or mixed‐mediated responses. To uncover the elusive immune mechanisms driving SEA, we performed single‐cell mRNA sequencing (scRNA‐seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, 5 controls and 6 with SEA. We identified six major cell types, including B cells, T cells, monocytes–macrophages, dendritic cells, neutrophils, and mast cells. All cell types exhibited significant heterogeneity, with previously identified and novel cell subtypes. Notably, we observed monocyte–lymphocyte complexes and detected a robust Th17 signature in SEA, with CXCL13 upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B‐cell population, Th17 polarization of the T‐cell populations, and dysregulation of genes associated with T‐cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T‐cell genes. The dysregulated genes identified through scRNA‐seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma.

Aspergillus fumigatus binding IgA and IgG1 are increased in bronchoalveolar lavage fluid of horses with neutrophilic asthma

“…Furthermore, anti-commensal IgG was shown to contribute to intestinal inflammation in ulcerative colitis in humans and a mouse model, including excessive Th17 responses and neutrophilic inflammation ( 69 ). The association of neutrophilic inflammation, increased antigen-binding IgG, and type 3 responses in mouse models matches the findings of increased IgG in EA shown here and previously ( 18 , 26 , 33 ) and the Th17 increase in SEA described in other studies ( 4 , 28 , 29 ).…”