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Resident tissue macrophages (RTM) can fulfill various tasks during development, homeostasis, inflammation and repair. In the lung, non-alveolar RTM, called interstitial macrophages (IM), importantly contribute to tissue homeostasis but remain little characterized. Here we show, using single-cell RNA-sequencing (scRNA-seq), two phenotypically distinct subpopulations of long-lived monocyte-derived IM, i.e. CD206⁺ and CD206⁻IM, as well as a discrete population of extravasating CD64⁺CD16.2⁺ monocytes. CD206⁺ IM are peribronchial self-maintaining RTM that constitutively produce high levels of chemokines and immunosuppressive cytokines. Conversely, CD206⁻IM preferentially populate the alveolar interstitium and exhibit features of antigen-presenting cells. In addition, our data support that CD64⁺CD16.2⁺ monocytes arise from intravascular Ly-6C^lo patrolling monocytes that enter the tissue at steady-state …