Abstract
Ischemic stroke causes rapid hypoxic damage to the core neural tissue which is followed by graded chronological tissue degeneration in the peri-infarct zone. The latter process is mainly triggered by neuroinflammation, activation of inflammasomes, proinflammatory cytokines, and pyroptosis. Besides microglia, astrocytes play an important role in the fine-tuning of the inflammatory network in the brain. Lipocalin-2 (LCN2) is involved in the control of innate immune responses, regulation of excess iron, and reactive oxygen production. In this study, we analyzed LCN2 expression in hypoxic rat brain tissue after ischemic stroke and in astrocyte cell cultures receiving standardized hypoxic treatment. Whereas no LCN2-positive cells were seen in sham animals, the number of LCN2-positive cells (mainly astrocytes) was significantly increased after stroke. In vitro studies with hypoxic cultured astroglia revealed that LCN2 expression is significantly increased after only 2 h, then further increased, followed by a stepwise decline. The expression pattern of several proinflammatory cytokines mainly followed that profile in wild type (WT) but not in cultured LCN2-deficient astrocytes. Our data revealed that astrocytes are an important source of LCN2 in the peri-infarct region under hypoxic conditions. However, we must also stress that brain-intrinsic LCN2 after the initial hypoxia period might come from other sources such as invaded immune cells and peripheral organs via blood circulation. In any case, secreted LCN2 might have an influence on peripheral organ functions and the innate immune system during brain hypoxia.
Highlights
Ischemic stroke is one of the most common neurological diseases worldwide causing disability and death [1]
In a first set of experiments, we aimed at investigating whether ischemic stroke induces an increase in LCN2 expression within the peri-infarct cortical brain area
We found a stepwise increase of LCN2 mRNA (Figure 1A) in brain tissue with a significant induction at 24 and 72 h post stroke
Summary
Ischemic stroke is one of the most common neurological diseases worldwide causing disability and death [1]. Astrocytes are critically involved in the maintenance of cellular functions in the brain under physiological and pathological conditions They scavenge reactive oxygen species (ROS) and excessive neurotransmitters, control ion and water efflux, release of neurotrophic factors, and control transport mechanisms through the blood–brain barrier (BBB) [2]. Astrocytes are part of the regulatory loops of brain intrinsic inflammatory processes and reactive astrocytes are a hallmark of many neuropathological events Upon activation, they undergo severe morphological and functional changes. Reactive astrocytes may inhibit axon regeneration and neuronal plasticity [4] They are involved in the regulation of water and ion homeostasis, cerebral blood flow, and control of the extracellular level of glutamate, as well as being the source of a variety of neuroprotective factors [5]. Microglia cells, probably the most important brain resident innate immune cell population, are potent astrocyte activators [7]
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