Determining spatial location of cells within tissues gives vital insight into the interactions between resident and inflammatory cells and is a critical factor for uncoupling the mechanisms driving disease. Here, we apply single-cell spatial transcriptomics to reveal the airway wall landscape in health and during asthma. We identified proinflammatory cellular ecosystems that exist within discrete spatial niches in healthy and asthma samples. These cellular hubs are characterized by a high level of chemokine and alarmin expression, along with unique combinations of stromal cells. Mechanistically, we demonstrated that receptors, such as ACKR1, retain immune mediators locally, while amphiregulin-expressing mast cells are prominent within these proinflammatory hubs. Despite anti-inflammatory treatments, the asthma airway mucosa exhibited a distinct remodeling program within these cellular ecosystems, marked by increased proximity between key cell types. This study provides an unprecedented view of the topography of the airway wall, revealing distinct, specific ecosystems within spatial niches to target for therapeutic intervention.