Bone marrow derived elements and resident microglia in brain inflammation

Abstract

Infection of the central nervous (CNS) system by the human immunodeficiency virus (HIV) depends on the migration of infected hematogenous cells into the brain. We thus used quantitative light and electron microscopic immunocytochemistry to study the homing and turnover of bone marrow derived cells in the CNS in radiation bone marrow chimeras under normal conditions and in experimental autoimmune encephalomyelitis (EAE) as an experimental model of brain inflammation. Our studies suggest the following conclusions. First, the central nervous system is continuously patrolled by a small number of T-lymphocytes and monocytes. Meningeal and perivascular monocytes are slowly replaced by hematogenous cells under normal conditions, and this turnover is accelerated in the course of inflammation. In contrast, resident microglia represent a very stable cell pool, which in adult animals is only exceptionally replaced by hematogenous cells, even after recovery from severe brain inflammation. Second, although in bone-marrow-chimeric animals resident microglia, astrocytes, and ependymal cells are not able to present antigen to Lewis T-lymphocytes, the inflammatory reaction in EAE is qualitatively and quantitatively similar in these animals compared to fully histocompatible Lewis rats. Finally, resident microglia express the macrophage activation antigen ED1. Thus, microglia cells appear to function as effector cells in EAE lesions.

Early and Rapid Engraftment of Bone Marrow-Derived Microglia in Scrapie

“…For many years, microglia were thought to be essentially sessile and to undergo only minor exchanges with peripheral monocyte-macrophage compartments (Hickey and Kimura, 1988;Lassmann et al, 1993). However, the present data indicate that microglia are extensively recruited from bone marrow to brain during the incubation period of scrapie.…”

The origin and differentiation of microglial cells during development

“…Hickey and Kimura (1988) showed that the perivascular microglia are bone marrow-derived. In contrast, very few parenchymal microglial cells of donor origin were observed despite the fact that non-microglial cells derived from the graft were common within the nervous parenchyma of normal and pathological brains (Hickey and Kimura, 1988;Hickey et al, 1992;Lassmann et al, 1993). These authors suggested that parenchymal microglia were of neuroectodermal origin, or that they derived from bone marrow-derived precursors which enter the nervous system before or about the time of birth.…”

Rod-Shaped Monocytes Patrol the Brain Vasculature and Give Rise to Perivascular Macrophages under the Influence of Proinflammatory Cytokines and Angiopoietin-2

“…In contrast, microglia are considered "resting" cells that need to be activated to manifest their full potential. This functional difference may explain why perivascular macrophages are continuously replenished by circulating monocytes, whereas microglia turn over very slowly, if at all, under normal conditions (Matsumoto and Fujiwara, 1987;Hickey and Kimura, 1988;Hickey et al, 1992;Lassmann et al, 1993;Bechmann et al, 2001a,b;Vallières and Sawchenko, 2003). Nevertheless, a significant number of microglia can be replaced by monocytes in response to injury or disease (Popovich and Hickey, 2001;Priller et al, 2001;McMahon et al, 2002;Kokovay and Cunningham, 2005;Ladeby et al, 2005;Schilling et al, 2005;Simard et al, 2006;Remington et al, 2007).…”