Therapeutic Effect of Modulating TREM-1 via Anti-inflammation and Autophagy in Parkinson's Disease.

Chien-Wei Feng,Chien-Liang Chen,Zhi-Hong Wen,Han-Chun Hung,Nan-Fu Chen,Chun-Sung Sung,Bing-Hung Chen,Wu-Fu Chen,San-Nan Yang,Hsiao-Mei Kuo

doi:10.3389/fnins.2019.00769

Abstract

Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases, and neuroinflammation has been identified as one of its key pathological characteristics. Triggering receptors expressed on myeloid cells-1 (TREM-1) amplify the inflammatory response and play a role in sepsis and cancer. Recent studies have demonstrated that the attenuation of TREM-1 activity produces cytoprotective and anti-inflammatory effects in macrophages. However, no study has examined the role of TREM-1 in neurodegeneration. We showed that LP17, a synthetic peptide blocker of TREM-1, significantly inhibited the lipopolysaccharide (LPS)-induced upregulation of proinflammatory cascades of inducible nitric oxide synthase (iNOS), cyclooxygenase-2, and nuclear factor-kappa B. Moreover, LP17 enhanced the LPS-induced upregulation of autophagy-related proteins such as light chain-3 and histone deacetylase-6. We also knocked down TREM-1 expression in a BV2 cell model to further confirm the role of TREM-1. LP17 inhibited 6-hydroxydopamine-induced locomotor deficit and iNOS messenger RNA expression in zebrafish. We also observed therapeutic effects of LP17 administration in 6-hydroxydopamine-induced PD syndrome using a rat model. These data suggest that the attenuation of TREM-1 could ameliorate neuroinflammatory responses in PD and that this neuroprotective effect might occur via the activation of autophagy and anti-inflammatory pathways.

Highlights

Neurodegenerative diseases (NDs) are permanent conditions of the central nervous system (CNS); in 2015, ND was ranked as the third leading cause of death in high-income countries, with 60 deaths per 10,000 people
We suggested that triggering receptor expressed on myeloid cells (TREM)-1 could express in microglia and regulate its own expression, FIGURE 4 | TREM-1 knockdown in BV2 cells decreased TREM-1 expression levels and the LPS-induced upregulation of iNOS, COX-2, and IκB expression and increased HDAC6 expression and the LC3-II/LC3-I ratio. (A) Western blot analysis of TREM-1 expression in the control siRNA and TREM-1 siRNA groups for 7 h (n = 4/group)
The results demonstrate that the transfection of TREM-1 siRNA significantly attenuated the expression of TREM-1. (B) Western blot analysis for iNOS, COX-2, and IκB expression in TREM-1 knockdown BV2 cells in the control, LPS-treated, control (TREM-1 siRNA), and LPS-treated (TREM-1 siRNA) groups after treatment with 100 ng/ml LPS for 16 h (n = 4/group)

Summary

Introduction

Neurodegenerative diseases (NDs) are permanent conditions of the central nervous system (CNS); in 2015, ND was ranked as the third leading cause of death in high-income countries, with 60 deaths per 10,000 people. Some recent studies depicted that among all causes of NDs, neuroinflammation played a crucial role, especially in NDs, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (Kempuraj et al, 2016; Ransohoff, 2016). Neuroinflammation is primarily mediated by microglial cell over activation, which was suggested to enhance the release of inflammatory enzymes (Ransohoff, 2016; Villegas-Llerena et al, 2016). Recent studies showed that inhibition of lipopolysaccharide (LPS)-induced inflammatory responses, including the production of nitride oxide (NO) and prostaglandin E2 (PGE-2), might reduce PD symptoms more than clinical drugs can (Liberatore et al, 1999; Sairam et al, 2003; Teismann et al, 2003; Wallace and Del Soldato, 2003; Rocha et al, 2015; Tentillier et al, 2016). Only few studies have investigated the effect of modulation of the upstream inflammatory signaling [i.e., triggering receptor expressed on myeloid cells (TREM) family] in PD (Liu et al, 2016; Tan et al, 2016)

Methods

Results

Discussion

Conclusion