Study Identifies Pathogenic Cell States, Transcriptional Programs Specific to Asthma

A new investigation identified pathogenic cell states and transcriptional programs exclusive to asthma and provided further details into the mechanisms that may be associated with allergic airway inflammation and structural remodeling.

In particular, airway epithelial cells (AEC) in allergic asthmatics (AA) were shown to upregulate mucus metaplasia, matrix-remodeling, and glycolytic programs while failing to upregulate antioxidant genes.

Notably, interleukin (IL)-9 expressing pathogenic TH2 were unique to asthmatic airways, which suggested that IL9 signaling may be fundamental to asthma pathogenesis.

The data were presented during a late-breaker session at the American Thoracic Society 2020 International Conference in San Francisco.

Though asthma is an important risk factor for asthma, it remains unknown as to who certain people with allergies develop asthma.

An investigative team led by Jehan Alladina, MD, Massachusetts General Hospital, hypothesized that comparing AA to allergic non-asthmatic control (AC) would identify pathways contributing to asthma pathogenesis compared to those with allergy alone.

As such, the team utilized a human model of asthma exacerbation and single-cell RNA-sequencing (scRNA-deq) to thoroughly define the airway mucosal landscape in these 2 groups of patients.

Alladina and colleagues isolated 52,152 cells for scRNA-seq from endobronchial brushings from AA and AC patients (4 samples per group) at baseline and 24 hours after segmental allergen challenge (SAC).

From there, mixed-effects logistic regression identified cells associated with either AC (OR<1) or AA (OR>1), and differentially expressed gene (DEG) were identified in AA versus AC after SAC.

The team observed that the airway landscape changed from predominantly AEC at baseline to immune cells after SAC.

A subcluster analysis identified 14 AEC clusters along with the first identification of lower airway hillock cells.

Compared to AC, investigators found that AEC in allergic asthmatic had dramatically altered patients’ transcriptional programs following allergen challenge in addition to upregulated mucus metaplasia, matrix-remodeling, and glycolytic genes. Contrastingly, AEC upregulated an antioxidant program in AC.

Furthermore, pathogenic TH2 were enriched in asthmatic airways after SAC (OR 3.43), and IL9 was uniquely expressed in TH2 in AA, which was implicated in mast cell activation and expression of pro-fibrotic mediators.

After SAC, immature CCR2-high monocyte-derived cells (MC) were enriched in AA, and an upregulation of an IL-13-induced transcriptional program was also observed.

In comparison, macrophage-like MC that upregulated pro-resolution genes involved in phagolysosmal and tissue repair were enriched in AC after SAC.

“Our data suggest a novel role for IL-13 in arresting CCR2-high MC in an immature and pro-inflammatory state, thereby preventing differentiation into macrophage-like MC that may resolve inflammation and promote tissue repair,” the team wrote.