PPARα ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways

Abstract

Whole-brain irradiation (WBI) can lead to cognitive impairment several months to years after irradiation. Studies on rodents have shown a rapid and sustained increase in activated microglia (brain macrophages) following brain irradiation, contributing to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Thus, alleviating microglial activation following radiation represents a key strategy to minimize WBI-induced morbidity. We hypothesized that pre-treatment with peroxisomal proliferator-activated receptor (PPAR)α agonists would ameliorate the pro-inflammatory responses seen in the microglia following in vitro radiation. Irradiating BV-2 cells (a murine microglial cell line) with single doses (2-10 Gy) of 137 Cs γ-rays led to increases in 1] the gene expression of IL-1β and TNFα, 2] Cox-2 protein levels and 3] intracellular ROS generation. In addition, an increase in the DNA-binding activity of redox-regulated proinflammatory transcription factors AP-1 and NF-κB was observed. Pre-treating BV-2 cells with the PPARα agonists, GW7647 and Fenofibrate significantly inhibited the radiation-induced microglial pro-inflammatory response, in part, via decreasing i] the nuclear translocation of the NF-κB p65 subunit and ii] phosphorylation of the c-jun subunit of AP-1 in the nucleus. Taken together, these data support the hypothesis that activation of PPARα can modulate the radiation-induced microglial pro-inflammatory response.

Corilagin inhibits the double strand break-triggered NF-κB pathway in irradiated microglial cells

“…Recent studies indicate that irradiation induces microglia activation in vitro, which leads to a marked increase level of pro-inflammatory cytokines (1,14,15). Radiation-induced microglia activation may play a role in RIBI since pro-inflammatory cytokines inhibit neurogenesis.…”

“…Microglia cells react to a variety of stimuli, including lipopolysaccharides (LPS), interferon-Á, and ß-amyloid. It was reported recently that microglia are activated post-irradiation (1). Upon activation in vitro, microglia produce a variety of pro-inflammatory mediators and cytokines, such as IL-1ß, IL-6, and TNF-·, reactive oxygen, nitric oxide (NO), and prostaglandin E (PGE 2 ), which are thought to be responsible for inflammation-related diseases, including radiation-induced brain injury (RIBI), trauma, ischemia, Alzheimer's disease, and neural death (2).…”

Role of nuclear receptors in breast cancer stem cells

“…For example, they can significantly reduce the levels of pro-inflammatory cytokines such as IL-1, the expression of TNFα, COX-2 and an inducible form of the enzyme nitric oxide synthase in murine microglia BV-2 exposed to radiation. This effect is due to the inhibition of translocation of the NFkB-p65 subunit or the inhibition of phosphorylation c-jun, a subunit of the transcription factor AP-1, both involved in inflammatory mechanisms [81] . MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype.…”

Radiation-induced cognitive impairment

“…A robust inflammatory reaction in the mouse dentate subgranular zone (SGZ) was observed 9 months after exposure to heavy-ion radiation [59] . A quick and persistent activated microglia (brain macrophages) in both the granule cell layer and the hilus following cranial radiation exposure also contribute to a chronic inflammation [60] . While activation of immune system by radiation therapy can facilitate tumor cell killing, radiation-induced chronic inflammation can cause adverse effects.…”

“…The alteration of neurogenesis was associated with a significant inflammatory response and oxidative stress [59,76,78] . Thus blockade of neuroinflammation using anti-inflammatory drugs such as indomethacin, the peroxisomal proliferator-activated receptor (PPAR) alpha agonist fenofibrateetc [60,61] , or blockade of oxidative stress using free radical scavengers such as edaravone and melatonin etc. [52,79] can protect neural progenitor cells from radiation-induced damage and preserve neurogenesis after irradiation.…”