Macrophages in spatial context: cellular niches in lung disease

Advances in spatial omics are shifting the study of lung macrophages from the characterization of isolated transcriptional states toward an understanding of their function in the context of cellular origin, anatomical location, neighboring cells, and tissue architecture. Here, we distinguish the macrophage niche in the strict sense-the local microenvironment that sustains tissue-resident macrophage survival and identity-from the broader cellular niche, in which macrophages are spatially organized with multiple interacting cell populations, and integrate recent insights into lung repair and chronic remodeling. Following injury, remodeling of the resident macrophage compartment, recruitment of monocyte-derived macrophages, and the emergence of regenerative epithelial intermediates and stromal responses generate transient multicellular environments that normally resolve as tissue homeostasis is restored. Spatial analyses, however, indicate that in at least some lung diseases, these repair-associated states fail to resolve and instead become organized into pathological cellular niches characterized by recurrent proximity among aberrant epithelial cells, inflammatory and profibrotic macrophages, activated stromal cells, and extracellular matrix. We further propose a spatial framework in which shared immune-epithelial-stromal interactions can give rise to distinct fibrotic architectures depending on whether they are anchored within alveolar-interstitial regions or around small airways. Finally, we discuss how pathological cellular niches identified by spatial approaches can be functionally validated and translated into therapeutically actionable intercellular circuits.