Reactive microgliosis engages distinct responses by microglial subpopulations after minor central nervous system injury

Abstract

Microglia are bone marrow-derived cells that constitute a facultative macrophage population when activated by trauma or pathology in the CNS. Endogenous CNS-resident microglia as well as exogenous (immigrant) bone marrow-derived cells contribute to reactive microgliosis, raising fundamental questions about the cellular composition, kinetics, and functional characteristics of the reactive microglial cell population. Bone marrow chimeric mice reconstituted with green fluorescent protein-expressing (GFP(+)) donor bone marrow cells were subjected to entorhinal cortex lesion, resulting in selective axonal degeneration and a localized microglial reaction in the hippocampus. Flow cytometric evaluation of individually dissected hippocampi differentiated immigrant GFP(+) microglia from resident GFP(-) microglia (CD11b(+)CD45(dim)) and identified a subset of mainly resident CD11b(+) microglia that was induced to express CD34. The proportion of immigrant GFP(+) microglia (CD11b(+)CD45(dim)) increased signficantly by 3 and 5 days postlesion and reached a maximum of 13% by 7 days. These cells expressed lower CD11b levels than resident microglia, forming a distinct subpopulation on CD11b/CD45 profiles. The proportion of CD34(+)CD11b(+) microglia was significantly increased at 3 days postlesion but had normalized by 5 and 7 days, when the microglial reaction is known to be at its maximum. Our results show that distinct subpopulations of microglia respond to minor CNS injury. The heterogeneity in microglial response may have functional consequences for repair and possibly therapy.

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

“…Both folate deficiency and excess methionine can slow the synthesis of nucleic acids, thereby inhibiting proliferation. Theoretically, such a phenomenon might have a greater impact on vascular and glial cells that, in contrast to the relatively quiescent neurons, retain their proliferative potential in the adult brain (42,43). Although we do not know whether the capillary rarefaction in this study was the result of homocysteine-mediated endothelial death or vascular remodeling, it is notable that adult cerebral microvasculature is capable of rapid and reversible angiogenic changes in response to metabolic stimuli.…”

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

“…The EC and hippocampus were carefully dissected from individual mice and prepared as described previously (15,43,44,56,57). Briefly, a single cell suspension was prepared using the plunger from a 1-cc syringe and a 70-m mesh (BD Biosciences).…”

“…This was achieved by using a stereotactic surgical model to localize mechanical damage to the EC of mice (15,(43)(44)(45). This stab lesion provokes junctional breakdown of the blood brain barrier in the EC, but not in the adjacent hippocampal regions of the brain where there is anterograde degeneration of transected axons and localized glial response (46,47).…”

Population Control of Resident and Immigrant Microglia by Mitosis and Apoptosis

“…7 Microglia are unique cells in the CNS parenchyma, being innate immune cells and having a mesodermal origin. In line with their myeloid lineage, 8 slow microglial turnover in normal CNS 9 and enhanced recruitment during reactive microgliosis 10,11 indicate that microglia are potentially replaceable cells, making microglia and their myeloid progenitors promising candidates for active cellular therapy in CNS disease and injury. 12,13 For potential microglial cell therapy to be safe and applicable for the treatment of neurological disease, information is needed about the population control of immigrating microglia that become involved in the microglial reaction.…”