Interleukin-4 Aggravates LPS-Induced Striatal Neurodegeneration In Vivo via Oxidative Stress and Polarization of Microglia/Macrophages

Jaegeun Jang,Byungkwan Jin,Ahreum Hong,Youngcheul Chung

doi:10.3390/ijms23010571

Abstract

The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or for hydroethidine histochemistry at the indicated time points after LPS injection. Analysis by NeuN and Nissl immunohistochemical staining showed a significant loss of striatal neurons at 1, 3, and 7 days post LPS. In parallel, IL-4 immunoreactivity was upregulated as early as 1 day, reached a peak at 3 days, and was sustained up to 7 days post LPS. Increased levels of IL-4 immunoreactivity were exclusively detected in microglia/macrophages, but not in neurons nor astrocytes. The neutralizing antibody (NA) for IL-4 significantly protects striatal neurons against LPS-induced neurotoxicity in vivo. Accompanying neuroprotection, IL-4NA inhibited activation of microglia/macrophages, production of reactive oxygen species (ROS), ROS-derived oxidative damage and nitrosative stress, and produced polarization of microglia/macrophages shifted from M1 to M2. These results suggest that endogenous IL-4 expressed in LPS-activated microglia/macrophages contributes to striatal neurodegeneration in which oxidative/nitrosative stress and M1/M2 polarization are implicated.

Highlights

Oxidative/nitrosative stress is a condition produced by the imbalance between oxidants and antioxidants [1], which results in the generation of excessive levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS) such as superoxide radical anion (O2 − ) and nitric oxide (NO) [2]
We investigated whether IL-4 that is endogenously expressed within activated microglia is associated with neurodegeneration by regulating oxidative/nitrosative stress and microglial polarization in the LPS-induced striatum in vivo
Brain sections were processed for Nissl staining and immunohistochemical staining for neuron-specific nuclear protein (NeuN) to identify general striatal neurons at the indicated time points

Summary

Introduction

Oxidative/nitrosative stress is a condition produced by the imbalance between oxidants and antioxidants [1], which results in the generation of excessive levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS) such as superoxide radical anion (O2 − ) and nitric oxide (NO) [2]. Accumulating evidence suggest that oxidative/nitrosative stress has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease [5,6,7], and can be a potential therapeutic target for the treatment of neurodegenerative diseases. M1-like microglia produce proinflammatory molecules, including inducible nitric oxide synthase (iNOS) [14], whereas M2-like microglia remove cellular debris through phagocytosis and release anti-inflammatory molecules, including arginase (Arg1) [15]

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Discussion

Conclusion