Activation of Microglia during Developmentally Regulated Cell Death in the Cerebral Cortex

Abstract

Neuronal elimination in the developing CNS is accomplished by an orderly type of cellular suicide called programmed cell death. The principal non-neuronal cells implicated in regulating programmed cell death and subsequent phagocytosis of dying neurons are the brain’s macrophage population, the microglia. Little is known about the signaling between microglia and neurons during programmed cell death. However, macrophages in non-neural tissues express receptors for immunoglobulin (IgG) and complement, and these molecules help regulate phagocytosis of dying cells and foreign organisms. Since many of the neurons generated early in CNS development are transient cell types that are immunoreactive for IgG [Upender et al.: J Comp Neurol 1997; 384:271–282], we hypothesized that IgG might alter the phagocytic properties of microglia within the developing nervous system and potentiate engulfment of dying cells. To begin to address this hypothesis, we first asked whether cortical neurons immunoreactive for IgG or calbindin-D28k exhibit morphological evidence of programmed cell death in the cerebral cortex of neonatal rat pups. Secondly, we quantified the incidence of contacts made by microglia on IgG- vs. calbindin-immunoreactive neurons. Thirdly, perturbation experiments were performed to elevate intracortical levels of IgG and the incidence of microglia:neuron contacts were determined. We found that although the nuclei of some IgG-immunoreactive neurons exhibited condensation and fragmentation characteristic of programmed cell death, we did not observe pyknotic calbindin-immunoreactive neurons. IgG-immunoreactive neurons were also more likely to be contacted by microglia than calbindin-immunoreactive neurons. Elevating intracortical levels of IgG experimentally led to a dramatic increase in the expression of microglia complement receptors throughout the cerebral cortex. Taken together, these results suggest that IgG normally present within neuronal subsets in the developing cerebral cortex could serve to locally regulate the expression of complement receptors on microglia.

B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice

“…When antibodies bind antigen, they form immune complexes (ICs) that cause tissue injury through activation of complement or recruitment/activation of cells bearing receptors for IgG, the FcRs (19)(20)(21)(22)(23)(24)(25)(26). To determine whether these mechanism(s) contribute to the pathology and loss of function caused by SCI antibodies, control or SCI antibodies were injected into the intact spinal cord of mice deficient in complement component C3 (C3 -/-) or the FcR γ chain (FcRg -/-).…”

Keeping the CNS clear: Glial phagocytic functions in Drosophila

“…Similarly, excessive neuronal branches and synapses have to be removed during development in order to shape the precise network of neuronal connections. Dying cells and pruned neuronal branches are eliminated efficiently, mostly by microglia (blood-derived tissue-resident professional phagocytes) and astrocytes in vertebrates (Farina et al, 2007;Napoli and Neumann, 2009;Upender and Naegele, 1999;Vilhardt, 2005;Yang et al, 2010) and by various types of glia in Drosophila (Awasaki and Ito, 2004;Kurant et al, 2008;Mallat et al, 2005;Marin-Teva et al, 2004;Sonnenfeld and Jacobs, 1995;Watts et al, 2004). Moreover, surplus presynaptic material and immature synaptic boutons that are generated during normal neuronal activity must be rapidly engulfed and degraded (Fuentes-Medel et al, 2009).…”

Immune reactivity in a mouse model of familial ALS correlates with disease progression

“…Interestingly, uptake of IgG by developing neurons is one of the mechanisms regulating detection, docking, and phagocytosis of apoptotic cells, with the Fc portion of IgG triggering microglial activation through the microglial FcR, and resulting in phagocytic transformation and subsequent removal of dying neurons. 24 Microglial cells are part of an innate immune system that might actively contribute to disease progression in mutant SOD1 transgenic mice rather than just performing a scavenging function. In support of this hypothesis, we found extensive microglial activation before the onset of clinical symptoms and prior to evidence of significant motor neuron loss.…”