Macrophage heterogeneity in tissues: phenotypic diversity and functions

Abstract

During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation.

Keywords: Tissue macrophages; heterogeneity; macrophages; markers; monocytes; phenotype.

Figure 1

Immunocytochemistry illustrates the differential staining of macrophages in mouse liver and spleen. Kupffer cells (A) and splenic red pulp macrophages (B) are strongly F4/80⁺, unlike F4/80⁻ marginal metallophils (C), which express CD169 strongly, and red pulp macrophages, which are CD169 dim or negative. Images (A) and (B) courtesy of D. A. Hume, image (C) courtesy of P. R. Crocker.

Figure 2

A subpopulation of CD169⁺ metallophils binds the cysteine-rich domain of the mannose receptor (CyR-Fc) (A), and associates with IgD⁺ B lymphocytes (B). Images courtesy of L. Martinez-Pomares. Reference should be consulted for further details.

Figure 3

Heterogeneity of F4/80⁺ cells in 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 fivefold variation in the density of immunostained microglial processes between different regions. More microglia are found in gray matter than white. 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 fiber tracts and possess several long processes which are usually aligned parallel to the longitudinal axis of the nerve fibers. 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 sensitive to their microenvironment. Drawings to illustrate the morphological heterogeneity of macrophage populations of the central nervous system: A,C,D show microglia of the brain parenchyma (A, cortex; B, white matter; C, ventral pallidum). Macrophages with a simpler morphology are also present in the circumventricular organs (B), the meninges (E), and choroid plexus (F). Based on which should be consulted for further details. Image courtesy of L. J. Lawson and V. H. Perry.

Figure 4

BCG-induced granulomata. BCG-induced granulomata in mouse liver express F4/80 antigen (A). These recruited macrophages are distinct in distribution from Kupffer cells and monocytes in sinusoids and express lysozyme mRNA strongly and uniformly (B). Images courtesy of D. A. Hume and S. Keshav. See Martinez-Pomares and Gordon for further details.