The Prompt Microglial Macrophage Response in Necrotic CNS Lesions

1. Microglial Responses to Stab Wounds and Bacterial Infection

In CNS injury leading to neuronal necrosis with breakdown of the blood-brain barrier (BBB), micro-glia are promptly activated and aided by infiltrating monocytes/macrophages from the circulation. As stated previously, at the stage of phagocytic transformation microglia and macrophages become indistinguishable by morphological grounds and by immunocytochemistry. Therefore, the population of phagocytes is referred to as microglia/macrophages in this article. The normal CNS appears to be relatively resistant to leukocyte diapedesis since intracerebral injections of proinflammatory cytokines such as IL-8, IL-1, and TNF-a elicit only minimal monocytic recruitment into the CNS parenchyma. However, necrotic brain lesions induce prompt inflammation. The critical role of breakdown of the BBB to macrophage recruitment into CNS lesions was demonstrated in the following experiment: Blood monocytes were prelabeled to allow follow-up of their distribution after injury. Although a mechanical CNS lesion with breakdown of the BBB led to prompt recruitment of these prelabeled peripheral monocytes, degeneration of inferior olivary neurons induced by intraperitoneal administration of 3-acetylpyridine, a neurotoxic process that respects the integrity of the BBB, led to microglial activation only.

The most simple traumatic CNS lesion with destruction of the BBB is a stab wound. A device is penetrated into the cortex. The ensuing cellular response is limited to the site of penetrating injury and the immediately surrounding tissue. Giulian and colleagues described activation of microglia at the lesion edges and infiltration of the wound site by hematogenous macrophages within hours after injury. Microglia proliferated locally with a maximum on Days 2 or 3, and mononuclear phagocytes rapidly cleared trauma-induced debris and produced IL-1, a cytokine that stimulates astrogliosis and neovascularization. Macrophages are attracted to tissues by chemokines. After penetrating mechanical CNS injury, astrocytes and endothelial cells increased mRNA levels of the che-moattractant monocyte chemoattractant protein-1 (MCP-1) and within 12 hr expressed MCP-1 protein, followed by prompt macrophage infiltration.

Microglia are involved in the formation of bacterial brain abscesses. Brain abscesses were produced experimentally in the rat by direct intracerebral injection of agarose beads laden with Staphylococcus areus. This approach allowed a sequential analysis of glial and inflammatory responses during different stages of abscess development. The first stage, acute cerebri-tis, was characterized by brain edema and diffuse infiltration of a wide rim of edematous brain parenchyma by microglia/macrophages around a necrotic center filled with granulocytes. Between Days 4 and 8 chronic cerebritis developed and microglia strongly upregulated CD4 and MHC class II molecules. At this stage increasing numbers of hematogenous macrophages were recruited and gathered around the necrotic lesion. This finally led to capsule formation, regression of the abscess, and resolution of the edema. Interestingly, a subpopulation of macrophages recognized by the antibody ED2 in the rat preferentially infiltrated brain abscesses. Their functional properties in comparison to those of the usual population of ED1+/ED2~ macrophages in other brain lesions have not been characterized.

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