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

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.

The inflammatory injury in the striatal microglia-dopaminergic-neuron crosstalk involved in Tourette syndrome development

“…It can regulate the polarization of the peripheral macrophage phenotype and inhibit the production of inflammatory mediators, such as interleukin-1b and TNF-a (66-69). However, it has been reported that IL-4 expressed in LPS-activated microglia contributes to striatal neurodegeneration, in which M1/M2 polarization is implicated, and the neutralizing antibody for IL-4 can protect striatal neurons against LPS-induced neurotoxicity in vivo (70). Also, we noticed increased IL-10 expression in the striatum of individual TS, despite its anti-inflammatory factor.…”

Exploring the mechanism of luteolin by regulating microglia polarization based on network pharmacology and in vitro experiments

“…Compared to traditional cell lines, primary microglia simulate in vivo biochemical reactions more faithfully, and the relevant experimental results obtained will be more reliable 37 , 38 . LPS is recognized for controlling microglia's M1-type polarization and facilitating the release of pro-inflammatory proteins, both of which support neuroinflammatory responses 48 , 49 . We cultured LPS-stimulated microglia with luteolin and identified that the expression of iNOS was downregulated, while the content of Arg-1 showed an upward trend (Fig.…”

Long-term intake of thermo-induced oxidized oil results in anxiety-like and depression-like behaviors: involvement of microglia and astrocytes

“…The activated microglia comprise two subtypes, the proinflammatory microglia (M1) and the anti-inflammatory microglia (M2). 37,38 The M1 microglia produce pro-inflammatory factors and reactive oxygen species, and M2 microglia release anti-inflammatory factors and neurotrophic factors (Fig. 3B).…”

“…Activated microglia can be classified into two states: classical activation (M1) and alternative activation (M2). 37 M1 microglia produce pro-inflammatory cytokines like TNF-α, IL-1β, IL-6 and NOS2. 60 On the other hand, M2 microglia remove cell debris through phagocytosis and release anti-inflammatory molecules such as IL-10, IL-4, Arg1, and ornithine.…”