Macrophages

Introduction

Macrophage

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Macrophages are large, round cells that contain a central round nucleus and have abundant clear, often vacuolated, cytoplasm. Macrophages acts as sentinel cells; they have a role in destroying bacteria, protozoa and tumour cells, and release substances that act upon other immune cells. They are also responsible for clearing dead and damaged cells and tissue through the process known as efferocytosis. Macrophages are phagocytic, long lived and are found throughout the body.

Development

Macrophages are either derived from blood borne monocytes which have migrated into tissue and differentiated, or from dividing macrophages within the tissue.

Locations

Macrophages are present throughout the body with large numbers in the lymph nodes, bone marrow and spleen. In connective tissue macrophages are fixed and referred to as tissue histocytes. Sentinel macrophages in the lung are called alveolar macrophages, while in the liver they are called Kupffer cells. In the brain they are microglia with long cytoplasmic processes.

Variations

Epithelioid cells

Epithelioid cells look like squamous epithelial cells with a pink (eosinophilic) cytoplasm and indistinct borders. They may be binucleate and tend to remain in the lesion. It is thought by some people that they may not phagocytose, but instead secrete substances directed against the foreign agent.

Giant cells

Macrophages can fuse together to form giant cells (Langhan’s cells), which with their greater cytoplasmic volume and number of lysosomes are able to engulf and deal with large foreign particles/bodies. They are thought to form when two or more macrophages attempt to engulf the same organism; the resulting cell can contain between two to several hundred nuclei per cell).

The nuclei can be scattered throughout the cytoplasm, clumped in the centre in foreign body granulomas or appear in a horseshoe shape at the periphery of the cytoplasm at one end in tuberculosis and some other granulomas. In the past, the morphology of these giant cells was correlated with the agent responsible for inflammation, although the distinction is not absolute.

Actions

Phagocytosis

Macrophages are phagocytic and take up particles and cell debris by endocytosis, as well as engulfing pathogens like bacteria through the specialist function of phagocytosis. These are then present in the macrophage inside phagosomes. Lysosomes present in the cytoplasm then bind with the phagosome and release their contents which degrade/digest its contents. The degradation of the lysosomal contents occurs in much the same way as neutrophils with both oxygen-dependent and oxygen-independent mechanisms.

Recognition

To function correctly macrophages need to correctly identify material that is either foreign (non-self) or which requires removal, such as damaged cells. They are able to recognise some foreign material directly (for example Lipopolysaccharide (LPS)) but in other circumstances proteins (opsonins) that bind to bacteria are required to increase the chances of successfully binding the foreign material to the macrophage. Some examples of opsonins include complement component C3bi and bound antibody.

Killing

This occurs using either oxygen dependant pathways or oxygen independent pathways.

Oxygen dependant killing requires the production of reactive oxygen species (ROS)(O₂^-), hydrogen peroxide (OH), reactive nitrogen species (RNS) (nitric oxide (NO)) and chlorine (Cl*) free-radicals that damage bacterial membranes (OH + Cl* = HOCl (otherwise known as bleach!)). These reactive species are generated during a burst of respiration following phagocytosis where increased amounts of oxygen are produced. Hydrochloric acid (HCl) is also produced during this process.

Oxygen independent killing uses lysosomes, cathepsin (a protease) and other mechanisms. Lysozymes are particularly effective against gram positive bacteria as they hydrolyse the glycopeptide coating of the bacterial organisms.

Antigen Presentation

Macrophages also act as antigen presenting cells taking antigens to lymph nodes to present to T cells. MHC II (major histocompatibility complex II) proteins on their surface allow them to interact with helper T cells (CD4). Short peptide segments from foreign cells are presented with MHC II which activates the T cell as part of the adaptive immune response.

Immune System Regulation

Macrophages are important players in orchestrating the various parts of the immune response. Tissue macrophages are responsible for the trigger of the innate immune response to an injury by releasing pro-inflammatory cytokines, in particular IL-1, IL-6 and TNF-α, that are responsible for the activation of the endothelium of post-capillary venules that allows neutrophils and other immune cells to adhere and extravasate (move out of the blood). With interactions with mast cells they amplify the release of vasoactive peptides including histamine and bradykinin. The cytokines IL-1, IL-6 and TNF-α along with the vasoactive peptides are responsible for the five signs of inflammation:(redness (rubor), heat (calor), swelling (tumor), and pain (dolor), often accompanied by loss of function). Systemic activation of macrophages leads to the condition known as septic shock.

In the latter course of inflammation, it is the blood monocytes, along with dendritic cells that switch the immune system from innate to adaptive (see above) by interacting with CD4⁺ T helper cells.

Chemotaxis

Macrophages are needed throughout the inflammatory response to perform their functions, with phagocytosis and the initiation of the inflammatory response by encouraging neutrophil extravasation, right through to the resolution of inflammation and/or the initiation of the adaptive immune response. At each of the stages of inflammation there are specific chemoattractants that the macrophages respond to. When the injury first occurs, it is the peptides released by bacteria (in particular formylated Met-Leu-Phe) and cytokines release by cells adjacent to the injury that bring the tissue macrophages into contact with the injured site. At the later stages, it is cytokines released by immune cells themselves that bring blood monocytes (blood macrophages) to the injury, beginning the adaptive immune response.

To migrate through connective tissue they release proteases and glycoaminoglycanases through a process called exocytosis (granule fusion with the plasma membrane).

Role in pathology

Macrophages are seen in both acute and chronic inflammation.

If large numbers of macrophages are found in chronic inflammatory processes, it implies the inability to eliminate the causal organism e.g. Mycobacterium (TB), Actinobacillus, fungi, parasites and foreign bodies.

Macrophages Learning Resources
PowerPoint Selection of relevant PowerPoint tutorials	Tutorial about connective tissues, with slides on Macrophages

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