A Deep Dive into the Functional Heterogeneity of Interstitial Macrophages 9108

Abstract Description Interstitial macrophages (IMs) are critical for tissue homeostasis and immunity, attracting significant attention since their discovery. In this study, we present a comprehensive transcriptomic analysis of murine lung IMs, uncovering their multifaceted nature and distinct roles beyond chemokine expression. Building on prior findings that chemokine-expressing IMs regulate immune cell recruitment and tertiary lymphoid tissue architecture. Using bioinformatics analyses, we demonstrate how IMs differential expression of cytokines, along with their corresponding cytokine and chemokine receptor genes, forming an extensive autocrine regulatory network that influences their migration and cytokine-mediated functions. We also identify distinct innate immune gene expression profiles, including genes involved in the complement system, scavenger receptor activity, and pattern recognition pathways, emphasizing their innate immune roles. Using Xenium spatial transcriptomics, we reveal that CD206hi and CD206lo IMs occupy distinct lung sub-tissular niches, likely driven by their differential expression of integrin and metallopeptidase genes. Our spatial and molecular analyses enhance our understanding of IM specialization, emphasizing their roles in tissue homeostasis and regulating immune responses, and lays the groundwork for future studies on their functions in health and disease. Funding Sources Supported by R01 HL115334 (C.V.J.); NIH grants R01 HL135001 (C.V.J.); NIH grants R35 HL155458 (C.V.J.) Topic Categories Mucosal and Regional Immunology (MUC)