Regulation of macrophage and dendritic cell responses by their lineage precursors

Abstract

Tissue macrophages (Mø) and dendritic cells (DC) are thought to derive from hematopoietic stem cells, which exist in the bone marrow and generate intermediate precursor populations with increasingly restricted lineage potentials. There exists several precursors committed to the Mø and DC lineages; these cells exhibit distinct tropism and function and respond differentially in pathophysiologic conditions. In this review, we consider experimental contexts in which Mø and DC responses in tissue are not only dictated by the local environment, but also by the quantity and quality of newly recruited lineage precursor cells. Consequently, we discuss whether therapeutic control of Mø and DC responses in tissue may be achieved through manipulation of their lineage precursors.

Fig. 1

Ontogeny of mononuclear phagocytes. The origin of DC and Mø populations can be tracked back to uncommitted HSC that reside in the bone marrow. Differentiation toward the mononuclear phagocyte lineage involves the generation of cell intermediates, which progressively lose their capacity to produce other lineages. Known cell intermediates include: common myeloid progenitors (CMP), granulocyte and Mø progenitors (GMP) and MDP. MDP represent the most committed progenitor that DC and Mø have in common. They give rise to pDC and cDC via a CDP and a pre-DC intermediate. MDP also give rise to two subsets of blood monocytes (Ly-6C^hi and Ly-6C^lo monocytes). Upon extravasation in tissue, Ly-6C^hi monocytes can differentiate into inflammatory Mø or monocyte-derived DC (Mø/DC), which resemble cDC, or TNF-α and iNOS-producing DC (Tip-DC). Ly-6C^lo monocytes, which may derive from Ly-6C^hi monocytes or MDP, can differentiate into Mø in tissue.

Fig. 2

Alteration of Mø/DC precursor responses in pathophysiologic conditions. This diagram reviews five scenarios in which mononuclear phagocyte precursors are involved. The responses mediated by these cells can affect tissue Mø and DC both quantitatively and qualitatively, and eventually have an impact on the course of the disease. The quantity of Mø/DC is controlled at least in part by the number of precursor cells that are mobilized, whereas the quality of Mø/DC is affected when defined precursor populations are mobilized. The diagram, which depicts HSC (grey dots), Ly-6C^hi monocytes (light blue dots), Ly-6C^lo monocytes (green dots), CDP/pre-DC/DC (red dots) and Mø/DC (dark blue dots), highlights how Ly-6C^hi monocyte responses can be amplified in vivo. However, similar mechanisms of action – which are not shown here – may apply to other precursor populations. a Dormant HSC residing in the bone marrow can be stimulated (e.g. by TLR ligands) to enter into a limited number of cell divisions and may differentiate toward the myloid lineage [85, 86]. This amplification process may produce Ly-6C^hi monocytes. b Select bone marrow precursor populations can be released in circulation [88]. For example, CCR2 signaling triggers the release of bone marrow Ly-6C^hi monocytes. c The spleen serves as a reservoir site for monocytes, which can be mobilized into circulation [76]. Defined stimuli may trigger the exit of Ly-6C^hi monocytes selectively. d Select precursor populations can be recruited to tissue [3, 96, 101, 109]. For example, production of MCP-1 by a disturbed tissue acts to recruit Ly-6C^hi monocytes. e A small fraction of HSC and progenitor cells exit the bone marrow and traffic through extramedullary tissues. These cells can be stimulated locally (e.g. by TLR ligands) to give rise to mononuclear phagocytes [92]. This amplification process may produce Ly-6C^hi monocytes and Mø/DC in inflamed tissues.