Review Article | Published:

Monocytes and macrophages: developmental pathways and tissue homeostasis

Nature Reviews Immunology volume 14, pages 392404 (2014) | Download Citation

Abstract

Monocytes and macrophages have crucial and distinct roles in tissue homeostasis and immunity, but they also contribute to a broad spectrum of pathologies and are thus attractive therapeutic targets. Potential intervention strategies that aim to manipulate these cells will require an in-depth understanding of their origins and the mechanisms that ensure their homeostasis. Recent evidence shows that monocytes do not substantially contribute to most tissue macrophage populations in the steady state or during certain types of inflammation. Rather, most tissue macrophage populations in mice are derived from embryonic precursors, are seeded before birth and can maintain themselves in adults by self-renewal. In this Review, we discuss the evidence that has dramatically changed our understanding of monocyte and macrophage development, and the maintenance of these cells in the steady state.

Key points

  • In steady-state conditions, blood monocyte subsets form in a developmental sequence with mouse LY6Chi monocytes giving rise to LY6Clow monocytes.

  • LY6Clow monocytes act within the vasculature by surveying the vessel wall for injury and LY6Chi monocytes are recruited to sites of inflammation and, after extravasation, differentiate in the tissue into cells with dendritic cell and macrophage activities.

  • Intestinal macrophages are continuously renewed by LY6Chi monocytes and thus differ from most other embryonic-derived tissue macrophages. LY6Chi monocytes are probably recruited in response to the tonic low inflammatory signals that are provided by the commensal gut microbiota. Other tissue macrophages that are derived from monocytes include dermal and heart macrophages.

  • Specific tissue-resident macrophage populations in mice are seeded before birth. At a very early stage, embryonic precursors — such as yolk sac-derived macrophages and fetal liver-derived monocytes — give rise to tissue macrophages that persist and maintain the macrophage pool into adulthood, without being superseded by adult bone marrow-derived or blood monocyte-derived cells.

  • Both yolk sac-derived macrophages and fetal liver-derived monocytes give rise to fetal macrophages. Their relative contribution to adult tissue macrophage populations varies between tissues and remains to be fully elucidated.

  • In adults, tissue macrophages maintain themselves by self-renewal at low levels in the steady state. Importantly, the ability of tissue macrophages to proliferate is enhanced during inflammation.

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Affiliations

  1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 138648 Singapore.

    • Florent Ginhoux
  2. Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.

    • Steffen Jung

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Florent Ginhoux or Steffen Jung.

Glossary

Mononuclear phagocyte system

(MPS). A term introduced by Van Furth that encompasses myeloid immune cells other than polymorphonuclear granulocytes and initially included monocytes and macrophages, and then, following their discovery, dendritic cells.

microRNA

(miRNA). A class of short endogenous non-coding RNAs that modulate the proteome through binding to complementary mRNAs and repressing translational initiation or by inducing mRNA degradation. This post-transcriptional regulation of gene expression depends on an imperfect match of short 'seed' sequences with their target mRNA and hence each miRNA has potential to suppress multiple targets.

Classical dendritic cells

(cDCs). A term introduced by Ralph Steinman that should be reserved for short-lived, FLT3 ligand-dependent cells with migratory capability and a potential to efficiently stimulate naive T cells.

Macrophage and DC precursor

(MDP). A bone marrow-resident LINCD117+CD135+ clonotypic precursor with plasmacytoid dendritic cell (pDC), classical DC (cDC) and monocyte potential.

Common monocyte progenitor

(cMoP). A bone marrow-resident LINCD117+ precursor with monocyte potential that is the direct progeny of macrophage and dendritic cell precursors (MDPs).

Intravital microscopy

A technique that is based on the combination of photonics, particularly multi-photon microscopy, and new molecular and genetic tools that enables imaging of tissues of living animals and is yielding insights into the mechanisms controlling immune cell motility and interactions in tissues.

Necrosis

A form of uncontrolled cell death caused by factors that are external to the cell or tissue — such as infection, toxins or trauma — that result in the unregulated destruction of cellular components.

Anticipatory inflammation

A recently coined term that describes the finding in mice that the abundance of circulating LY6Chi monocytes is under circadian control, which might have evolved to prepare the organism for insults.

Cre–loxP

A site-specific recombination system in which two short DNA sequences (loxP sites) are engineered to flank the target DNA and the expression of Cre recombinase leads to excision of the intervening 'floxed' sequence. Depending on the type of promoter, Cre recombinase can be expressed at specific times during development or in specific sets of cells.

Kupffer cells

Specialized macrophages of the liver that reside within the lumen of the liver sinusoids.

Langerhans cells

These cells were classically considered as a dendritic cell (DC) population that resides in the skin epidermis and are now considered as a DC–macrophage hybrid, as they are unique among DC subsets in that they arise from embryonic progenitors and are radio-resistant, long-lived and independent of FLT3 ligand. They also show considerable transcriptome overlap with macrophages.

Parabiotic mice

A model in which pairs of mice are surgically joined by cutaneous vascular anastomoses so that they have a common blood circulation while maintaining separate organs and tissues. A few weeks after the initiation of parabiosis, a steady state is achieved in these mice in which circulating leukocyte populations are stably comprised of cells that are derived from both animals.

Microglial cells

This cell type constitutes a radio-resistant, highly ramified macrophage population of the central nervous system that is derived from primitive yolk sac macrophages and contributes to brain development and homeostasis by synaptic pruning and debris clearance.

Primed homeostasis

The unique homeostatic 'alert state' of the intestinal mucosa, which is constantly exposed to microbial products.

Blood–brain barrier

A semipermeable cellular structure that separates the blood from the cerebrospinal fluid, and constitutes a barrier to the passage of cells, particles and large molecules into the brain parenchyma.

Experimental autoimmune encephalomyelitis

(EAE). A well-studied mouse model of the human disease multiple sclerosis, which is characterized by extensive infiltration of the central nervous system by inflammatory cells and involves the activation of pathogenic myelin-specific TH1 or TH17 cells.

Primitive haematopoiesis

Blood cell production that originates from the yolk sac and constitutes the first wave of haematopoiesis. It is transient and starts from murine embryonic day 7.0 in the extra-embryonic yolk sac where, shortly after the onset of gastrulation, the mesodermal layer develops into structures that are referred to as blood islands that predominantly produce nucleated erythrocytes and macrophages, but not lymphocytes.

Haematopoietic stem cells

(HSCs). Cells that have both the ability to generate all types of haematopoietic cell (multipotentiality) and to replace themselves (self-renewal) during the whole lifespan of an individual.

Aorta–gonads–mesonephros

(AGM). The embryonic site where definitive haematopoietic stem cells (HSCs) are produced. It comprises the aorta, and the developing reproductive and excretory (mesonephros) systems. Within this haemogenic site, HSCs are concentrated in the aorta region.

Definitive haematopoiesis

A process that occurs in the fetal liver in the embryo, during which blood cells are produced from haematopoietic stem cells (HSCs) that are generated initially in the splanchnopleura or aorta–gonads–mesonephros (AGM), and then in the bone marrow of adults. It is responsible for the generation of the multipotent HSCs with multi-lineage haematopoietic potential, which arise within the AGM from embryonic day 10.5.

Induced pluripotent stem cells

Also known as iPS cells (or iPSCs), these are a type of pluripotent stem cell that can be generated directly from adult cells by specific genetic reprogramming.

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