Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches

Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1^loMHCII^hiCX3CR1^hi (Lyve1^loMHCII^hi) and Lyve1^hiMHCII^loCX3CR1^lo (Lyve1^hiMHCII^lo) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (<i>Slco2b1</i> ^flox/DTR), we found that the absence of Lyve1^hiMHCII^lo IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.