Reactive astrocytes secrete lcn2 to promote neuron death

Abstract

Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.amyotrophic lateral sclerosis | astrocytosis G lial reaction is a common feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington disease, Parkinson disease, and Alzheimer's disease. Astrocytes and microglia become reactive during neurodegenerative processes (1, 2), and activated astrocytes may exhibit differential expression of astrocytic receptors, transporters, and transmitters; metabolic changes; and altered synthesis and release of proteins, chemokines, and cytokines (3-6). Controlled activation of astrocytes is considered beneficial to neurons (7), but overactive astrocytes can be harmful (8). Astrocytosis in neurodegeneration has been intensively studied, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined.Reactive astrocytes may lose neuroprotective functions or gain neurotoxic properties in neurodegenerative diseases. Astrocytes are responsible for the reuptake of the neurotransmitter glutamate, which is accomplished by excitatory amino acid transporter 2 (EAAT2 or GLT1) (9). In mice, GLT1 deficiency leads to synaptic glutamate accumulation and subsequent excitotoxicity (9). Astrocytes become reactive during neurodegeneration and gradually lose GLT1 function and expression (10-12). Stimulating GLT1 expression with antibiotics protects motor neurons in an ALS model (13). Because reactive astrocytes may lose their neuroprotective abilities, as observed during GLT1 deficiency (10-12), supplementing normal astrocytes to the areas of active neuropathology is expected to have a therapeutic effect. Indeed, transgenic rats with ALS are...

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation

“…Using gene expression profiling, we identified LCN2, with a 125‐fold induction in gene expression in BM‐MSC recipient retina, as a potential new marker of retinal reactive gliosis. There is increasing evidence correlating astrocyte‐mediated LCN2 secretion to neuroinflammation 28, 40, reactive gliosis 41, and neuronal death 40. Although the mechanism through which LCN2 signals is not yet clear, its expression has been reported to be mediated by the ERK1/2 and INFγ/STAT1 signaling cascade 29.…”

“…Moreover, in different models of neurodegeneration, LCN2 acts as chemokine inducer by promoting the upregulation of chemokines, such as CCL2 and CXCL10, through the JAK2/STAT3 pathway 28. There is evidence that under degenerative conditions reactive astrocyte gain neurotoxic properties and recent studies have identified LCN2 as an inducible neurotoxic mediator secreted by astrocytes to promote neuronal death 40. Based on this evidence, LCN2 secretion in the host retina following BM‐MSC transplantation suggests a potential detrimental glial response that needs to be modulated.…”

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

“…The major findings were (1) Brain LCN2 levels were increased in the caudate after ICH and intracerebral injection of Expression of LCN2 was found in astrocytes, microglia, neurons, and endothelial cells after ICH in mice. 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.…”

Lipocalin 2 modulates the cellular response to amyloid beta

“…26 Production of LCN2 by astrocytes was previously described both in vitro, in response to proinflammatory cytokines such as interferon-g and TNF, 17,26 and in vivo, in models of CNS neuroinflammatory diseases like experimental autoimmune encephalomyelitis 19 and spinal cord injury. 27 Interestingly, also microglial cells were shown to respond to LCN2, which seems to favor their polarization into a M1-activated phenotype.…”