Desferrioxamine Ameliorates Lipopolysaccharide-Induced Lipocalin-2 Upregulation via Autophagy Activation in Primary Astrocytes

Lipocalin-2 (LCN2) is an important regulator of both neuroinflammation and iron homeostasis. Upregulated LCN2 was observed in reactive astrocytes in the Parkinson's disease (PD) models. In the present study, we reported iron chelator deferoxamine (DFO) abolished lipopolysaccharide (LPS)-induced LCN2 upregulation in primary astrocytes, although iron overload had no effects. The suppressive effects of DFO were consistent with autophagy inducer rapamycin or carfilzomib, blocked by autophagy inhibitor 3-methyladenine rather than chloroquine or bafilomycin Al, meanwhile, while were not dependent on proteasome system and NF-kappa B pathway. DFO was not able to ameliorate LCN2 upregulation in alpha-synucleintreated astrocytes, because DFO failed to induce autophagy in these cells. We further demonstrated that DFO could not enhance autophagy lysosomal degradation, however promoted secretory autophagy in primary astrocytes with LPS insults. These data suggest that DFO could serve as an autophagy activator, capable of ameliorating the upregulation of LCN2 in astrocytes by acting on the formation of autophagosomes and secretory autophagy. This provides better understandings of DFO-mediated neuroprotection against neuroinflammation and provides new insights that autophagy activation could be beneficial approaches in PD.

Automated summary

In this study, it was discovered that iron chelator deferoxamine (DFO) can inhibit the upregulation of Lipocalin-2 (LCN2) in astrocytes, independent of iron overload. This inhibitory effect is similar to that of autophagy inducers and does not rely on the proteasome system or the NF-kappa B pathway. DFO also promotes secretory autophagy, which improves the upregulation of LCN2 in astrocytes.