Macrophage form, function, and phenotype in mycobacterial infection: lessons from tuberculosis and other diseases

Abstract

Macrophages play a central role in mycobacterial pathogenesis. Recent work has highlighted the importance of diverse macrophage types and phenotypes that depend on local environment and developmental origins. In this review, we highlight how distinct macrophage phenotypes may influence disease progression in tuberculosis. In addition, we draw on work investigating specialized macrophage populations important in cancer biology and atherosclerosis in order to suggest new areas of investigation relevant to mycobacterial pathogenesis. Understanding the mechanisms controlling the repertoire of macrophage phenotypes and behaviors during infection may provide opportunities for novel control of disease through modulation of macrophage form and function.

Keywords: granuloma; macrophage; mycobacteria; tuberculosis.

Figure 1.

Ontologic sources of macrophages during mycobacterial infection. Macrophages present in adult tissues are derived from embryonic and bone marrow sources. Embryonically derived macrophages establish residence in tissues during early development and are continuously derived from established tissue-specific precursors. Alternatively, adult bone marrow continuously gives rise to monocytes which differentiate into monocyte-derived macrophages in response to stimuli and migrate into tissues. During infection, mycobacteria are phagocytosed by alveolar macrophages, an embryonically derived lineage, shortly after inhalation. Infected alveolar macrophages migrate into the lung interstitum and are joined by recruited monocyte-derived macrophages, which aggregate together in order to form the granuloma structure. In this way, diverse macrophage populations collaborate to respond to infection and develop the granuloma.

Figure 2.

Structure and inflammatory arrangement of the tuberculosis granuloma. The granuloma is an organized aggregate of macrophages surrounded by a cuff of B and T lymphocytes. Plasma cells and dendritic cells are also granuloma associated. Within the granuloma, macrophages differentiate into additional cell types including epithelioid macrophages, MGCs and foamy macrophages. Different cell types are spatially organized within the granuloma with foamy macrophages found surrounding the necrotic lipid-rich core, epithelioid macrophages forming tight junctions around the central core and additional macrophages aggregating at the outer edge of the structure. The activation state of macrophages as well as the presence of pro-inflammatory and anti-inflammatory markers is also spatially arranged with more anti-inflammatory phenotypes at the periphery of the granuloma structure (pink) and more pro-inflammatory phenotypes in central regions (orange).