Path of differentiation defines human macrophage identity.

Macrophages play central roles in immunity, wound healing, and homeostasis - a functional diversity that is underpinned by varying developmental origins. The impact of ontogeny on properties of human macrophages is inadequately understood. We demonstrate that definitive human fetal liver (HFL) hematopoietic stem cells (HSCs) possess two divergent paths of macrophage specification that lead to distinct identities. The monocyte-dependent pathway exists in both prenatal and postnatal hematopoiesis and generates macrophages with adult-like responses properties. We now uncover a fetal-specific pathway of expedited differentiation that generates tissue resident-like macrophages (TRMs) that retain HSC-like self-renewal programs governed by the aryl hydrocarbon receptor (AHR). We show that AHR antagonism promotes TRM expansion and mitigates inflammation in models of atopic dermatitis (AD). Overall, we directly connect path of differentiation with functional properties of macrophages and identify an approach to promote selective expansion of TRMs with direct relevance to inflammation and diseases of macrophage dysfunction.