Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

https://courses.washington.edu/conj514/readings/heinecke_reading4.pdf

Monocyte and macrophage heterogeneity

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

/pdf/fate-mapping-analysis-reveals-that-adult-microglia-derive-4q8i4y2udw.pdf

Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages

Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.

Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

Blood Monocytes Consist of Two Principal Subsets with Distinct Migratory Properties

Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain

Turnover of resident microglia in the normal adult mouse brain

Cell-restricted membrane antigens have made it possible to map the distribution of mature macrophages in many murine tissues. Monoclonal antibodies (mAbs) have been used to define the appearance of macrophages dusing foetal and postnatal development, to establish the anatomic relationships between macrophages and other cells in the normal and diseased adult, and to investigate cellular modulation and heterogeneity within different microenvironments. Current studies have illustrated the complex differentiation pathway of mononuclear phagocytes in vivo and have raised questions concerning the mechanisms that determine monocyte entry, migration and fate within tissues. Macrophages constitute a major, widely dispersed system of cells that regulate homeostasis in the normal host and respond to tissue injury by contributing essential functions during inflammation and repair. In this review we consider several membrane marker antigens which have proved useful in studying the life history and biologic properties of macrophages, and relate immunochemical studies on antigen expression to lineage analysis and macrophage differentiation in vivo. We restrict our discussion to the mouse, in which it is possible to manipulate the system in its entirety. Where known, properties of macrophages in other species are broadly similar.

Antigen markers of macrophage differentiation in murine tissues.

The monoclonal antibody 2F8 was used to localize the macrophage scavenger receptor by immunohistochemistry. In control adult mice, macrophage scavenger receptor expression in the brain was restricted to stromal and epiplexus macrophages of the choroid plexus, meningeal macrophages and to perivascular sites. Microglia did not express the receptor. In the developing mouse brain, macrophage scavenger receptor expression was high on meningeal macrophages and detectable on immature microglia in the supraventricular corpus callosum, cingulum, cavum septum and the periaqueductal area. In the aged mouse brain, the pattern of macrophage scavenger receptor expression was no different from that in the young adult brain. Macrophage scavenger receptor expression on resident microglia and recruited macrophages was detected 24 h after an intrahippocampal injection of either lipopolysaccharide or kainic acid. Macrophage scavenger receptor expression was also detected in microglia 3 days after optic nerve crush both in the nerve segment distal to the crush site and in the superior colliculus. These studies indicate a potential role for the macrophage scavenger receptor in the CNS in the clearance of debris during acute neuronal degeneration.

Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS

Paneth cells in normal murine small intestine contain TNF mRNA that is readily detectable by in situ hybridization, unlike resident macrophages in lamina propria, which are negative. Northern blot analysis of whole tissue shows the presence of mRNA that has the same electrophoretic mobility as TNF mRNA from activated macrophages. A low level of TNF bioactivity, but no immunoreactivity, was detected in normal small intestine, and TNF production in resting Paneth cells appears to be post-transcriptionally controlled. Typical leukocyte surface membrane markers were not found on Paneth cells, but were expressed by the surrounding lamina propria macrophages. Paneth cells are thus epithelial cells with leukocyte-like secretory potential that may be important in intestinal physiology and pathology.

/pdf/tumor-necrosis-factor-mrna-localized-to-paneth-cells-of-37qzll14zv.pdf

L.J. Lawson

Papers

Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain

Turnover of resident microglia in the normal adult mouse brain

Antigen markers of macrophage differentiation in murine tissues.

Upregulation of the macrophage scavenger receptor in response to different forms of injury in the CNS

Tumor necrosis factor mRNA localized to Paneth cells of normal murine intestinal epithelium by in situ hybridization.