ArticleFrontiers in immunology2026
Molecular and spatial specialization of lung interstitial macrophage subsets: beyond chemokines.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Interstitial macrophages (IMs) are increasingly recognized for their vital roles in maintaining tissue homeostasis and orchestrating immune responses. Building on earlier work showing that two overarching IM subsets, CD206hi and CD206lo, encompass ten unique chemokine-expressing subpopulations that regulate immune cell recruitment and tertiary lymphoid structures, we sought to further define the molecular programs, potential divisions of labor, and spatial organization of murine lung IMs. Methods: We performed a comprehensive transcriptomic analysis of murine lung IMs and integrated these data with Xenium spatial transcriptomics to examine IM subset-associated gene programs and localization within the lung microenvironment. Differential gene expression across IM subsets is summarized in accompanying tables. Results: CD206hi and CD206lo IM subsets exhibited distinct cytokine and receptor gene profiles, along with a predicted autocrine network that may influence their migration and cytokine-driven functions. IM subsets also displayed distinct innate immune signatures, including complement components, scavenger receptors, and pattern recognition receptors, such as Toll-like receptors and C-type lectins. Using Xenium spatial transcriptomics, we found that IMs in our dataset predominantly localized to three lung regions: bronchovascular bundles, interstitium, and periphery. CD206hi and CD206lo IMs preferentially occupied specific anatomical niches, associated with differential integrin and metallopeptidase gene expression. Chemokine expression within IMs also showed distinct spatial localization patterns associated with the positioning of T cells and B cells. Discussion: Overall, our findings advance the understanding of IM heterogeneity and identify molecular programs associated with chemoattraction, inflammation regulation, innate immune defense, and tissue maintenance, while providing a high-resolution framework for investigating their localization, interactions, and contributions to lung immunity and disease.
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