Introduction

Cells of the mononuclear phagocyte system are widely distributed throughout every tissue of the body and their properties vary depending on their functional state and location. Macrophages are generated in the bone marrow and circulate in the blood as monocytes before crossing the vascular wall and entering the tissues. Once they have entered the tissue and have developed under the influence of the local environment, they are known as macrophages, or by more specialised names that were used prior to their identification as macrophages [1]. Thus liver macrophages are known as Kupffer cells, brain macrophages are microglial cells, and bone macrophages are osteoclasts. Importantly, tissue macrophages have very different functions depending on their locale. Thus spleen macrophages have a variety of functions that reflect their heterogeneity; the red pulp macrophages clear senescent red blood cells while the macrophages of the marginal zone and the lymphoid areas participate in the host response to infection. Similarly, the liver macrophages, or Kupffer cells, have a role in clearance of a wide variety of detritus. The osteoclasts are somewhat more exotic; they attach themselves to bone and remodel it by a specialised form of frustrated phagocytosis.

The homeostatic functions of tissue macrophages only partially represent the role of cells of the mononuclear phagocyte lineage. Macrophages are best known for their role in host defence and inflammation. Circulating monocytes are attracted to areas of infection by chemotactic agents; once there they become activated and acquire properties that facilitate effective defence against the pathogen. The cells bind pathogens via a variety of receptors, phagocytose them, and kill them within the ensuing vacuole [2]. The dead pathogen is degraded within the mature phagosome, also known as a phagolysosome, and microbial peptides are exported to the cell surface where they are presented to T cells. In this sense, macrophages, and their close relatives, the dendritic cells, initiate and orchestrate the adaptive immune response. This is a bi-directional relationship; activated T-cells produce cytokines like interferon-y that activate the macrophage to become a voracious killing machine. Macrophage activation is a two-edged sword. It is absolutely required for effective host defence, but the inflammatory sequellae is also harmful. Unbridled macrophage-mediated inflammation is the effector of a multitude of pathological states including many autoimmune diseases and heart disease. Despite these negative effects, inflammatory mediators produced by macrophages mainly have positive functions as they participate in processes such as wound healing, tissue remodelling and angiogenesis.

Monocytes, macrophages, dendritic cells and the related microglial cells are critical for immune surveillance in the brain |3J. Although this surveillance is a normal homeostatic process, it can cause inflammation and pathology if it goes awry. This balance is tightly controlled by a variety of cytokines and protein mediators. For example, tumour necrosis factor (TNFa) enhances immune surveillance whereas transforming growth factor P (TGFP) diminishes it. Similarly, pathogen-derived components such as bacterial lipopolysaccharides are capable of stimulating proinflammatory responses in the brain. A major goal of this review is the description of the mechanisms by which bacterial products stimulate proinflammatory responses.

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