A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma

Abstract

Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9 -expressing pathogenic T H 2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C ) and CCR2 -expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a T H 2–mononuclear phagocyte–basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.

Inflammatory and tolerogenic myeloid cells determine outcome following human allergen challenge

“…The exact mechanism determining whether a pro- or anti-inflammatory monocyte response is mounted remains to be determined. The presence of Th2 cells in the tissue of AR patients is a likely candidate (as demonstrated for the airways of patients with allergic asthma; Alladina et al, 2023 ; Cho et al, 2016 ), either or not boosted by local chemokines, as those were prominently found among differentially expressed ligand–receptor interaction pairs described in Fig. S4, E and F .…”

Increased glycolysis and cellular crosstalk in eosinophilic chronic rhinosinusitis with nasal polyps

“…This study highlights that macrophage soluble products may account for some of these discrepancies. Notably, recent studies in both humans and mice have identified the importance of macrophage-epithelial interactions in wound repair and asthma ( 37 , 38 ).…”

“…Interestingly, we also detected an interaction of basal EpC CCL26 with a different chemotactic receptor, CCR2 , on IL1B monocyte-derived macrophages in eCRSwNP, but not in FCER2 monocyte-derived macrophages or FN1 activated tissue-resident macrophages in eCRSwNP. Macrophages expressing CCR2 have been implicated in asthma pathogenesis due to their expansion after allergen challenge in human asthmatics ( 37 ) and have been identified as potential precursors for intra-epithelial macrophages and alternatively-activated macrophages in mouse asthma models ( 38 ). Whereas CCR2 is conventionally thought of as a receptor for the monocyte chemoattractant CCL2 (which encodes MCP-1), binding of CCL26 to CCR2 has been reported to prevent the ability of monocytes to response to monocyte chemokines such as MCP-1 ( 66 ); therefore we propose that this CCL26-CCR2 interaction may underlie the lack of expansion in IL1B monocyte-derived macrophages in eCRSwNP ( Supplementary Figure 1C ) compared to alternatively-activated macrophage populations ( Figure 1D ).…”

ERS International Congress 2023: highlights from the Basic and Translational Sciences Assembly

“…Further work utilising scRNAseq showed heterogeneity within Th2 cell populations and identified a subset of pathogenic IL-9-expressing Th2 cells that was increased in allergic asthmatic individuals compared to allergic individuals without asthma [ 72 ]. Strikingly, post-allergen challenge, Th2 cells were only present in the airways in asthma, and airway epithelial cells demonstrated a dramatically altered transcriptional response in subjects with asthma but not in those with allergy alone [ 73 ]. The online resource Human Lung Cell Atlas integrates multiple scRNAseq respiratory system datasets, facilitating disease comparisons at the single-cell level with the potential to identify novel targets for intervention [ 74 ].…”