IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia

Abstract

Tissue-specific Langerhans cells and microglia develop in situ before birth. Colonna and colleagues identify IL-34 produced by keratinocytes and neurons as the relevant ligand of CSF1R necessary for their generation. The differentiation of bone marrow–derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34LacZ/LacZ) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34LacZ/LacZ mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.