Induction of microglial toll-like receptor 4 by prothrombin kringle-2: a potential pathogenic mechanism in Parkinson's disease.

Won-Ho Shin,Un Ju Jung,Byung Kwan Jin,Sung Joong Lee,Eunju Leem,Kyoung Hoon Jeong,So-Yoon Won,Catriona Mclean,Sang Ryoung Kim,Min-Tae Jeon,Sang-Joon Park

doi:10.1038/srep14764

Abstract

Microglia-mediated neuroinflammation may play an important role in the initiation and progression of dopaminergic (DA) neurodegeneration in Parkinson’s disease (PD), and toll-like receptor 4 (TLR4) is essential for the activation of microglia in the adult brain. However, it is still unclear whether patients with PD exhibit an increase in TLR4 expression in the brain, and whether there is a correlation between the levels of prothrombin kringle-2 (pKr-2) and microglial TLR4. In the present study, we first observed that the levels of pKr-2 and microglial TLR4 were increased in the substantia nigra (SN) of patients with PD. In rat and mouse brains, intranigral injection of pKr-2, which is not directly toxic to neurons, led to the disruption of nigrostriatal DA projections. Moreover, microglial TLR4 was upregulated in the rat SN and in cultures of the BV-2 microglial cell line after pKr-2 treatment. In TLR4-deficient mice, pKr-2-induced microglial activation was suppressed compared with wild-type mice, resulting in attenuated neurotoxicity. Therefore, our results suggest that pKr-2 may be a pathogenic factor in PD, and that the inhibition of pKr-2-induced microglial TLR4 may be protective against degeneration of the nigrostriatal DA system in vivo.

Highlights

substantia nigra (SN) neuroinflammatory processes are crucial for the initiation and progression of Parkinson’s disease (PD), and that microglia, the resident immune cells of the brain, are important mediators of brain inflammation, which has been implicated in neurotoxicity[3,4]
Our observations showed that decreases in neuromelanin-positive neurons (DA neurons) were confirmed in SN sections from patients with PD compared with sections from age-matched controls (Fig. 1a), and many microglia that were stained with anti-Iba[1] had an activated morphology characterized by enlarged cell bodies with short processes (Fig. 1b)
The total level of Iba[1] and OX-42, which serves as a marker of microglial levels, was not significantly different between patients with PD and age-matched controls (Fig. 1c), even though there was a significant increase in tumor necrosis factor-alpha (TNF-α ) as a neurotoxic inflammatory cytokine, which could be produced by activated microglia, in the SN of patients with PD compared with age-matched controls (Extended data Fig. 1)

Summary

Introduction

SN neuroinflammatory processes are crucial for the initiation and progression of PD, and that microglia, the resident immune cells of the brain, are important mediators of brain inflammation, which has been implicated in neurotoxicity[3,4]. Microglia are important cells expressing TLR4, and TLR4-mediated signaling pathways within microglia stimulate the production of neurotoxic inflammatory cytokines[13,14,15] Increased levels of such cytokines have been implicated in the pathology of many diseases of the central nervous system, such as cerebral ischemia[16], traumatic brain injury[17], Alzheimer’s disease (AD)[18], and PD19. It remains unclear whether the levels of TLR4 are increased in the brains of patients with PD, and whether TLR4 induction in microglia is necessary for pKr-2-mediated neurotoxicity. We determined whether there is a correlation between pKr-2-induced neurotoxicity and microglial TLR4 expression in rodent models, and assessed the specific effects of intranigral injection of pKr-2, which caused disruption of nigrostriatal DA projections in the adult brain

Methods

Results

Conclusion