Signals governing monocyte differentiation during inflammation

Abstract

Monocytes are innate immune cells that develop in the bone marrow and are continually released into circulation, where they are poised to enter tissues in response to homeostatic or inflammatory cues. Monocytes are highly plastic cells that can differentiate in tissues into a variety of monocyte-derived cells to replace resident tissue macrophages, promote inflammatory responses, or resolution of inflammation. As such, monocytes can support tissue homeostasis as well as productive and pathogenic immune responses. Recent work shows previously unappreciated heterogeneity in monocyte development and differentiation in the steady state and during infectious, autoimmune, and inflammatory diseases. Monocyte-derived cells can differentiate via signals from cytokines, pattern recognition receptors or other factors, which can influence development in the bone marrow or in tissues. An improved understanding of these monocyte-derived cells and the signals that drive their differentiation in distinct inflammatory settings could allow for targeting these pathways in pathological inflammation.

Figure 1:. Bone marrow myelopoiesis during inflammation.

A) Development of DC-like and neutrophil-like monocytes in the bone marrow. HSCs and MPPs generate CMPs that are committed to the myeloid lineage, at which point monocyte development pathways diverge. CMPs can differentiate into MDPs that generate cMOPs, that in turn make DC-like monocytes. CMPs can also differentiate into GMPs that generate MPs, which then make neutrophil-like monocytes. In vivo treatment with LPS promotes the development of DC-like monocytes, whereas treatment with CpG DNA promotes the development of neutrophil-like monocytes. B) Emergency myelopoiesis promotes myelopoiesis over lymphopoiesis in response to infection or inflammation. This can be via direct signals, such as TLRs, on HSCs, MPPs, or CMPs or via indirect signals, such as cytokines made by other cells or progenitors themselves. C) In a zebrafish model, caspase-1 activation in HSCs caused the cleavage of GATA-1, a key transcription factor promoting megakaryocyte and erythrocyte development, leading to increased output of monocytes and neutrophils and reduced megakaryocytes and erythrocytes.

Figure 2:. Monocyte fates induced by inflammation.

A variety of inflammatory signals can act on myeloid progenitor cells or monocytes to induce differentiation into specialized monocyte-derived populations. Signals can act in a direct (e.g. Toll-like receptors) fashion or through indirect mechanisms (e.g. cytokines) to promote these cell fates. Different combinations of markers and gene expression patterns allow for the identification of monocyte-derived cell populations. TLR, Toll-like receptor; Hh colitis, Helicobater hepaticus-induced colitis; CHIKV, chikungunya virus; T. gondii, Toxoplasma gondii; MDP, Monocyte-DC Progenitor; GMP, Granulocyte Macrophage Progenitor; SatM, segregated-nucleus-containing atypical monocyte; iHPC, inflammatory hemophagocyte; moDC, monocyte-derived dendritic cell.