Role of lipocalin-2 in extracellular peroxiredoxin 2-induced brain swelling, inflammation and neuronal death

Exp Neurol. 2021 Jan;335:113521. doi: 10.1016/j.expneurol.2020.113521. Epub 2020 Oct 29.

Abstract

Peroxiredoxin-2 (PRX-2) is known to be released from erythrocytes and induce brain damage after intracerebral hemorrhage (ICH); lipocalin-2 (LCN-2) is involved in neuroinflammation following ICH. This study examined the role of LCN-2 in PRX-2 induced brain injury and involved three parts. In the first part, adult male C57BL/6 wild-type (WT), LCN-2 heterozygous (LCN-2 HET), and LCN-2 knockout (LCN-2 KO) mice received either an intracaudate injection of recombinant PRX-2 or saline. In the second part, adult male C57BL/6 WT and male LCN-2 KO mice received recombinant PRX-2 with either recombinant mouse LCN-2 protein or control. In the third part, adult female C57BL/6 WT, LCN-2 HET, and LCN-2 KO mice received recombinant PRX-2. Behavioral tests, and T2- and T2*- weighted magnetic resonance imaging was obtained for all mice. Mice were then euthanized, and their brains used for Western blotting, histology and immunohistochemistry. Intracerebral PRX-2 injections resulted in increased expression of LCN-2 protein. PRX-2-induced brain swelling, neutrophil infiltration, microglia/macrophage activation, neuronal cell death, and neurological deficits were reduced in male LCN-2 HET and LCN-2 KO mice (P < 0.01) compared to WT and were exacerbated by exogenous LCN-2 co-injection. Additionally, intracerebral PRX-2 injections caused brain injury and neurological deficits in female WT mice; effects reduced in female LCN-2 KO mice. In conclusion, intracerebral injection of PRX-2 upregulates LCN-2, and LCN-2 is crucial in the effects of PRX-2 on neutrophil infiltration and microglia/macrophage activation, and ultimately brain damage.

Keywords: Brain swelling; Intracerebral hemorrhage; Lipocalin-2; Microglia; Neutrophils; Peroxiredoxin-2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain Edema / chemically induced*
  • Brain Edema / genetics*
  • Brain Edema / pathology
  • Cell Death / genetics
  • Encephalitis / genetics*
  • Encephalitis / pathology
  • Female
  • Lipocalin-2 / biosynthesis
  • Lipocalin-2 / genetics*
  • Macrophage Activation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / pathology*
  • Neutrophil Infiltration
  • Peroxiredoxins*

Substances

  • Lipocalin-2
  • Lcn2 protein, mouse
  • Peroxiredoxins