A Dual Role of Lipocalin 2 in the Apoptosis and Deramification of Activated Microglia

Abstract

Activated microglia are thought to undergo apoptosis as a self-regulatory mechanism. To better understand molecular mechanisms of the microglial apoptosis, apoptosis-resistant variants of microglial cells were selected and characterized. The expression of lipocalin 2 (lcn2) was significantly down-regulated in the microglial cells that were resistant to NO-induced apoptosis. lcn2 expression was increased by inflammatory stimuli in microglia. The stable expression of lcn2 as well as the addition of rLCN2 protein augmented the sensitivity of microglia to the NO-induced apoptosis, while knockdown of lcn2 expression using short hairpin RNA attenuated the cell death. Microglial cells with increased lcn2 expression were more sensitive to other cytotoxic agents as well. Thus, inflammatory activation of microglia may lead to up-regulation of lcn2 expression, which sensitizes microglia to the self-regulatory apoptosis. Additionally, the stable expression of lcn2 in BV-2 microglia cells induced a morphological change of the cells into the round shape with a loss of processes. Treatment of primary microglia cultures with the rLCN2 protein also induced the deramification of microglia. The deramification of microglia was closely related with the apoptosis-prone phenotype, because other deramification-inducing agents such as cAMP-elevating agent forskolin, ATP, and calcium ionophore also rendered microglia more sensitive to cell death. Taken together, our results suggest that activated microglia may secrete LCN2 protein, which act in an autocrine manner to sensitize microglia to the self-regulatory apoptosis and to endow microglia with an amoeboid form, a canonical morphology of activated microglia in vivo.

Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway

“…Recent studies have suggested that neuroinflammation is accompanied by the activation of microglial cells and the release of inflammatory mediators, which activates cellular cascades and results in neural apoptosis in the brain [47,48] . Our results indicate that SalB blocks the CMS-induced increases in apoptosis in both the hippocampus and cortex and prevents the decrease of hippocampal volume and cell density.…”

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

“…Although LCN2 is considered as being mainly expressed in astrocytes, 12,14,23,24 where its secretion may be neurotoxic, 24 other cell types may express LCN2. Thus, inflammatory cells, such as microglia and neutrophils 15,25,26 can also express LCN2. The effects of LCN2 on microglia are complex.…”

Identification of Stage Biomarkers for Human African Trypanosomiasis

“…31 Moreover, astrocytes and microglia also express lipocalin 2 after inflammatory stimulation in vitro . 32,33 The SLPI, an anti-inflammatory protease inhibitor, 34 is expressed in neurons and astrocytes, but not in macrophages/microglia. The localization of SLPI in the peri-infarct zone after middle cerebral artery occlusion in rats, suggested its role in the suppression of the inflammatory response to the ischemia.…”