Tissue macrophages: heterogeneity and functions

Abstract

Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes in defence against microbes and in clearance of dead and senescent cells, but also through trophic, regulatory and repair functions. In this review, we describe macrophage phenotypic heterogeneity in different tissue environments, drawing particular attention to organ-specific functions.

Fig. 1.

Origins and distribution of tissue macrophages. During development, erythromyeloid progenitors from yolk sac and foetal liver give rise to tissue-resident macrophages which persist during adult life as long-lived cells of widely varying mophology that turn over locally. Around the time of birth, bone marrow haemopoietic stem cells (HSC) become the source of blood monocytes, replenishing resident populations with high turnover, such as gut, and in response to increased demand. Therefore, different tissues contain varying mixtures of embryo and marrow-derived macrophages. In response to inflammation, immune and pathologic responses, monocytes infiltrate tissues and give rise to activated macrophages with complex phenotypes. Chronic immune cell aggregates can give rise to macrophage-rich granulomas, containing multinucleated giant cells as a result of monocyte/macrophage fusion. Monocytes contribute to osteoclast multinucleation and also generate functional dendritic cells upon culture in GM-CSF, with or without IL-4. Distinct monocyte populations give rise to DC [111], activated [111] and fibrogenic [18] macrophages

Fig. 2.

Selected plasma membrane receptors that mediate macrophage recognition of microbial and host ligands. Macrophages are able to express a large repertoire of membrane receptors implicated in the recognition and uptake of foreign and modified self ligands, some of which are illustrated here. These receptors incorporate a range of structural domains, illustrated schematically; they serve as useful marker antigens for immunocytochemistry and FACS analysis (e.g. F4/80, CD68, CSF1 receptor, Mer-TK, CD64). They function as opsonic (antibody and or complement coated particles to enhance uptake via Fc and complement receptors) or non-opsonic, carbohydrate-binding lectins and scavenger receptors. The phagocytic receptors mediate clearance of microbes (e.g. MARCO), apoptotic cells (for example CD36, SR-A, TIM4) and circulating ligands; for example, CCR2 and CX3CR1 are receptors for the monocyte/macrophage chemokines MCP-1 and fractalkine, respectively, for growth promoting and regulatory cytokines, for example, CSF-1 and angiopoietins, (Tie-2), and CD163 for clearance of injurious haptoglobin–haemoglobin complexes. Toll-like receptor-4 and CD14 react with bacterial membrane components such as lipopolysaccharide (LPS) to induce pro-inflammatory signalling; Dectin-1 recognises fungi through beta glucan in their wall, activating a range of innate immunological responses. Siglec-1 (CD169), a receptor for sialic acid terminal glycoconjugates, mediates adhesion of host cells and microbes, whereas CD206, a receptor for clearance of Mannosyl terminal glycoproteins, is a prototypical marker of M2 activation. The scavenger receptor SR-A internalises polyanionic ligands such as modified lipoproteins, as well as selected microbes, whereas CD36 mediates adhesion and M2-induced macrophage fusion and giant cell formation. TREM-2 mutations have been implicated in neurodegeneration and osteoclast dysfunction (see [25] and text for further details)

Fig. 3.

Schematic illustration of F4/80 antigen expression by tissue-resident macrophages in the mouse. Monocytes and macrophages express F4/80 antigen after differentiation and proliferation of F4/80 negative precursors in the embryo (not shown) and bone marrow. Mature F4/80+ macrophages associate with endothelia and epithelia as they migrate through tissues. Monocytes (+/-) replenish F4/80+ tissue-resident macrophages, for example in gut, liver, skin and brain, and contribute to formation of F4/80-negative osteoclasts. Macrophages lining lung alveoli and in T-cell-rich lymphoid tissues express F4/80 weakly. See Gordon et al. [112] for further details

Fig. 4.

F4/80+ stromal macrophages in the bone marrow play a trophic role in haemopoiesis. Haemopoietic stem cells (HSC) associate with mesenchymal stromal cells in a specialised niche in the bone marrow during the early stages of haemopoiesis. After proliferation and differentiation, erythroblasts and myeloblasts associate with stromal F/80+ macrophages, forming haemopoietic islands with central macrophages. These stromal macrophages express non-phagocytic adhesion molecules, a divalent cation-dependent haemagglutinin and the sialic acid recognition receptor Siglec1 (CD169), which retain these committed haematopoietic cells for poorly defined trophic support, before they are ready for release into the circulation. In addition these stromal macrophages ingest erythroid nuclei and recycle Fe

Fig. 5.

Macrophages in different regions of the mouse spleen and lymph node perform distinct functions in immunity and haemopoietic cell turnover. Schematic representation of regional differences of splenic macrophages in the red and white pulp, as well as the marginal zone. Marginal zone metallophils line vascular sinuses. Lymph nodes contain an analogous population that lines the subcapsular sinus. See text for further details. From [113], with permission

Fig. 6.

Gut macrophages populate the lamina propria and the myenteric plexus and interact with the microbiome and immune cells as well as the epithelium, smooth muscle and nerves. a Lamina propria macrophages in the mouse small intestine express abundant F4/80 antigen, indicated by arrows. The T-cell-rich Peyer’s patch and dome epithelium (stars) in the centre of the micrograph are devoid of F4/80 expression. Intestinal lumen, asterisks. From [114], ©Hume et al., 1983. Originally published in The Journal of experimental medicine. http://doi.org/10.1084/jem.158.5.1522. b Schematic representation of intestinal cross section to show interactions of macrophages (blue) with myenteric and autonomic nervous system projections (green). The inset shows the nerve ending releasing neurotransmitter which is recognized by β2 adrenergic receptors (β2AR) on the macrophage. From [54], reprinted from Cell, 164, Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D, Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages, 378,©2016, with permission from Elsevier

Fig. 7.

Kupffer cells, monocytes and macrophages interact with sinusoidal epithelium, hepatocytes and immune cells. a Normal mouse liver. Sinusoids (asterisks) are bordered by F4/80+ Kupffer cells (arrows) and F4/80 negative endothelial cells (arrowheads), in close proximity to hepatocytes, which are often binucleated (broken arrow). b, c Granuloma formation. Macrophages in granulomas induced by the mycobacterial vaccine Bacille Calmette Guérin (BCG) express F/80 antigen (bold arrows) on a background of activated Kupffer cells (slender arrows) and activated monocytes (b); BCG-induced recruitment of activated monocytes in sinusoids (triangles) and M1 activated macrophages in granulomas (arrows), which express lysozyme strongly and uniformly, detected by in situ hybridisation. See [115] for further details

Fig. 8.

Morphological heterogeneity of F4/80+ microglia in the adult mouse brain. F4/80+ microglia are present in large numbers in all major divisions of the brain, but are not uniformly distributed. There is a more than five-fold variation in the density of immunostained microglial processes between different regions. More microglia are found in gray than in white matter. Microglia vary in morphology depending on their location. Compact cells are rounded, sometimes with one or two short thick limbs, bearing short processes. They resemble Kupffer cells of the liver and are found exclusively in sites lacking a blood–brain barrier. Longitudinally branched cells are found in fibre tracts and possess several long processes which are usually aligned parallel to the longitudinal axis of the nerve fibres. Radially branched cells are found throughout the neuropil. They can be extremely elaborate and there is wide variation in the length and complexity of branching of the processes. The systematic variation in microglial morphology provides evidence that these cells are exquisitely sensitive to their microenvironment. See [38] for further details. Camera lucida drawing courtesy of L.J. Lawson and V.H. Perry. The different panels show: a microglia in the cortex; b macrophages of the subfornical organ, one of the circumventricular organs lacking a blood brain barrier; c microglia of the white matter; d microglia in the ventral pallidum, one of the most densely populated regions of the central nervous system (note the smaller territories of the microglia); e macrophages of the meninges; f macrophages of the choroid plexus. In addition, the central nervous system contains perivascular macrophages which express F4/80 as well as the clearance receptors SR-A and CD206, which are downregulated in resident microglia in normal brain (not shown)