Abstract
Numerous studies have reported the importance of microglial activation in various pathological conditions, whereas little attention has been given to the point for dynamics of microglial population under infection-induced inflammation. In the present study, the single systemic stimulation of 100 μg/kg lipopolysaccharide (LPS) induced robust microglial proliferation only in the circumventricular organs (CVOs) and their neighboring brain regions. More than half of microglia similarly showed proliferative activity in the CVOs and their neighboring brain regions after 1 mg/kg LPS stimulation, while this stimulation expanded microglia-proliferating brain regions including the hypothalamus, medulla oblongata, and limbic system. Microglia proliferation resulted in a transient increase of microglial density, since their density almost returned to basal levels within 3 weeks. Divided microglia survived at the same rate as non-divided ones. Proliferating microglia frequently expressed a resident microglia marker Tmem119, indicating that increase of microglia density is due to the proliferation of resident microglia. Thus, the present study demonstrates that transient increase in microglia density depends on the brain region and dose of LPS during infection-induced inflammation and could provide a new insight on microglia functions in inflammation and pathogenesis of brain diseases.
Highlights
Deficient for fractalkine receptor that is involved in the adhesion and migration of microglia and other immune cells reveal lower brain levels of amyloid-β and amyloid deposits in an Alzheimer’s model mouse[11]
We attempted to elucidate the proliferation of resident microglia in mouse brain during LPS-induced inflammation: (1) brain region-dependent heterogeneity; whether LPS-induced microglial proliferation is limited to the circumventricular organs (CVOs) or occurs in other brain regions; (2) dose-dependent difference; whether microglial proliferation is induced by LPS stimulation at the dose of 100 μg/kg as well as 1 mg/kg; (3) endogenous microglia proliferation; whether microglia density is increased by the proliferation of brain-resident microglia or the infiltration of circulating immune cells; (4) fate of proliferated microglia; how long increased density of microglia is maintained and whether divided microglia survive or die
The results obtained provide evidence for marked increases in microglial proliferation in the CVOs and their neighboring brain regions during mild inflammation induced by a single systemic LPS stimulation at a dose of 100 μg/kg
Summary
Deficient for fractalkine receptor that is involved in the adhesion and migration of microglia and other immune cells reveal lower brain levels of amyloid-β and amyloid deposits in an Alzheimer’s model mouse[11] This is due to an overall greater phagocytic capacity by higher proliferative activity of microglia and subsequent increase of their number around individual plaques. The present study is the first demonstration for brain region-dependent heterogeneity of transient and robust microglia proliferation during infection-induced inflammation. Such microglia proliferation is induced by low dose of LPS, indicating that a transient increase in microglia population could occur during mild inflammatory stimulation
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