Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages

Abstract

The explosion of new information in recent years on the origin of macrophages in the steady-state and in the context of inflammation has opened up numerous new avenues of investigation and possibilities for therapeutic intervention. In contrast to the classical model of macrophage development, it is clear that tissue-resident macrophages can develop from yolk sac-derived erythro-myeloid progenitors, fetal liver progenitors, and bone marrow-derived monocytes. Under both homeostatic conditions and in response to pathophysiological insult, the contribution of these distinct sources of macrophages varies significantly between tissues. Furthermore, while all of these populations of macrophages appear to be capable of adopting the polarized M1/M2 phenotypes, their respective contribution to inflammation, resolution of inflammation, and tissue repair remains poorly understood and is likely to be tissue- and disease-dependent. A better understanding of the ontology and polarization capacity of macrophages in homeostasis and disease will be essential for the development of novel therapies that target the inherent plasticity of macrophages in the treatment of acute and chronic inflammatory disease.

Keywords: Kupffer cells; M1M2; adipose tissue macrophages; hepatic steatosis; microglia; neurodegenerative disease; obesity; tissue-resident macrophages.

Figure 1

Differentiation of resident macrophages in various physiological states. (A) Two tissue macrophage populations reside in bone, F4/80⁻ TRAP⁺ osteoclasts and F4/80⁺ CD169⁺ TRAP⁻ tissue-resident macrophages (MΦs). Osteoclasts are developmentally dependent on Mac3⁺F4/80⁻ monocytes but only during inflammation. Alternatively, tissue-resident macrophages in bone can be maintained by a heme-induced subset of monocytes (CD11b^hi Ly6C⁺ SPI-C⁻). (B) Cardiac tissue-resident macrophage populations are primarily yolk sac-derived (YS) however a minor subset of the population is derived from fetal liver and HSC-derived progenitors. In homeostasis, primary yolk sac-derived cardiac resident macrophages are maintained through self-renewal but in response to cardiac insult, Ly6C^hi monocytes contribute to all four macrophage populations. (C) Selective transcriptional control plays an important role in the development of different types of macrophage populations. While red-pulp macrophages are dependent on SPI-C activity for development and maintenance, marginal zone (MZ) macrophage differentiation is mediated by LXRα. Alternatively, Gata6 is mandatory for the differentiation and proliferation of peritoneal macrophages while GM-CSF-dependent induction of PPARγ regulate alveolar macrophage development.

Figure 2

Microglial–neuronal interactions in health and disease. Healthy neurons expressing chemokine fractalkine (CX₃CL1) and CD200 membrane proteins intimately interact with their respective transmembrane protein receptors on microglia, CX₃CR1, and CD200R to sustain a down-regulated microglial phenotype. Microglial receptors have immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which upon ligand–receptor activation suppresses downstream immune signaling through the recruitment of phosphatases including SHP-1. Chronic inflammation disrupts this intimate neuronal–glial interaction, thus releasing the microglial cells from a down-regulated inhibited state to an activated phenotype.

Figure 3

Homeostatic regulation of ATM microenvironment. Healthy adipose tissue contains a relatively low and uniformly dispersed population of alternatively activated M2 macrophages, expressing cell surface antigens CD206 and CD301. The M2 polarized state is maintained by eosinophil and adipocyte derived adipokine secretions, IL-4, and adiponectin, respectively. M2 ATMs maintain a homeostatic adipose milieu with IL-10 secretions, which in turn regulate glucose homeostasis within systemic tissues.

Figure 4

The dual role of M1/M2 Kupffer cells in NAFLD. Kupffer cells play a pivotal role in host defense where they routinely clear microbes and apoptotic bodies from portal circulation. During diet-induced liver injury, tissue-resident macrophages exhibiting a classically activated M1 phenotype predominate and secrete cytokines that can alter hepatocyte lipid metabolism and induce MCP-1 dependent recruitment of monocytes into the liver. In turn, these infiltrating cells facilitate the development and progression of NAFLD. Restrained induction of M1 Kupffer cell apoptosis further perpetuates liver inflammation.

Figure 5

Resident macrophage populations in steady state and inflammation. Resident microglia and Kupffer cell populations, both yolk sac-derived, are maintained through self-renewal, unlike macrophages resident to the adipose tissue, which are thought to originate from circulating blood monocytes (MO). Although the progression of tissue specific pathophysiological insults are dependent on both resident and infiltrating macrophages, monocyte-derived macrophages do not replenish resident microglia and Kupffer cell populations.