Tissue resident macrophages are long-lived cells that are distributed throughout the body and migrate into the tissue during embryogenesis. They are specialized in ingesting and processing dead cells, debris and foreign materials, and in the recruitment of other immune cells – like monocytes – to sites of injury in response to inflammatory signals. Monocytes, on the other hand, represent short-lived cells that can be found in the peripheral circulation. Traditionally, it was assumed that monocytes represent an intermediate stage, linking mononuclear phagocyte precursors in the bone marrow with terminally differentiated tissue resident macrophages. However, this concept seems to hold true only for certain tissues, which are characterized by low-grade steady state inflammation. In most of the cases, embryo-derived tissue macrophages are endowed with an intrinsic self-renewal program to maintain homeostasis, while monocyte descendants are devoid of this capacity. Instead, monocytes are highly plastic cells and can differentiate – depending on the cellular context – into various cell types with fundamental different functions like effector monocytes, monocyte-derived dendritic cells and monocyte-derived macrophages.
The transcription factor C/EBPβ is expressed in cells of the myeloid lineage, especially in monocytes, macrophages and dendritic cells. Recently, we applied epigenetic approaches to identify C/EBPβ as one of the main regulators of monocyte development under physiological conditions. Deficiency of C/EBPβ in mice let to a complete absence of Ly6C- monocytes due to impaired induction of the monocytic survival factor Nr4a1. However, the functional role of C/EBPβ during differentiation of other myeloid populations in vivo is still enigmatic.
We are currently investigating the differentiation of myeloid cells under steady state as well as pathological conditions in various tissues using epigenetic approaches including ATACseq, ChIPseq and Crispr/Cas9-modified mouse models. The central concept is to identify new factors involved in differentiation that regulate and control the fate of monocytes and macrophages under homeostatic and pathological conditions.
Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007 Dec;10(12):1544-53.
Mildner A, Schönheit J, Giladi A, David E, Lara-Astiaso D, Lorenzo-Vivas E, Paul F, Chappell-Maor L, Priller J, Leutz A, Amit I, Jung S. Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C- Cells. Immunity. 2017 May 16;46(5):849-862
Varol D, Mildner A, Blank T, Shemer A, Barashi N, Yona S, David E, Boura-Halfon S, Segal-Hayoun Y, Chappell-Maor L, Keren-Shaul H, Leshkowitz D, Hornstein E, Fuhrmann M, Amit I, Maggio N, Prinz M, Jung S. Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain. Immunity. 2017 Jun 20;46(6):1030-1044
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
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