Tissue imprinting defines functional mosaic of dermal macrophages

Dermal macrophages (macs) protect the skin from invading pathogens. They are derived from embryonic as well as hematopoietic progenitors. However, the functional impact of their diverse origin and the control networks defining different subsets remain unclear. Here, using multidimensional analysis of dermal macs, we reveal that the absence of circulating monocytes in interferon regulatory factor 8 ( Irf8 ) deficient mice delays mac renewal during the steady state. Yet, the functional mosaic of dermal macs remains largely intact, i.e., major dermal mac subsets develop independently of monocyte replenishment. Thus, the tissue microenvironment is sufficient to induce alternative differentiation pathways and functional specialization of resident cells. Mycobacterial skin infection induces a steep increase in mac density due to monocyte-derived macs which execute urgent antibacterial functions and differentiate into site-adapted mac subsets in wildtype but not Irf8 ^-/- mice, while long-term resident macs are required to initiate a tissue repair program already in early stages of infection.

In summary, we introduce a model, where an intricate network of specialized mac subsets develops to meet microanatomical needs and external cellular input is required only during immunological emergency situations.