Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration.

Yun Gao,Dezhen Tu,Hui-Ming Gao,Chun-Hsien Chu,Ru Yang,Jau-Shyong Hong

doi:10.3390/ijms21020465

Abstract

Chronic neuroinflammation contributes to the pathogenesis of Parkinson’s disease (PD). However, cellular and molecular mechanisms by which chronic neuroinflammation is formed and maintained remain elusive. This study aimed to explore detailed mechanisms by which anti-inflammatory cytokine interleukin-10 (IL-10) prevented chronic neuroinflammation and neurodegeneration. At 24 h after an intranigral injection of lipopolysaccharide (LPS), levels of NLRP3, pro-caspase-1, pro-IL-1β, active caspase-1, and mature IL-1β in the midbrain were much higher in IL-10−/− mice than wildtype mice. Mechanistically, IL-10−/− microglia produced more intracellular reactive oxygen species (iROS) and showed more profound activation of NADPH oxidase (NOX2) than wildtype microglia. Meanwhile, suppression of NOX2-derived iROS production blocked LPS-elicited caspase-1 activation and IL-1β maturation in IL-10−/− microglia in vitro and in vivo. One month after intranigral LPS injection, IL-10−/− mice revealed more profound microglial activation and dopaminergic neurodegeneration in the substantia nigra than wildtype mice. Importantly, such PD-like pathological changes were prevented by IL-1β neutralization. Collectively, IL-10 inhibited LPS-elicited production of NOX2-derived iROS thereby suppressing synthesis of NLRP3, pro-caspase-1 and pro-IL-1β and their activation and cleavage. By this mechanism, IL-10 prevented chronic neuroinflammation and neurodegeneration. This study suggested boosting anti-inflammatory effects of IL-10 and suppressing NLRP3 inflammasome activation could be beneficial for PD treatment.

Highlights

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by progressive loss of dopamine (DA) neurons in the substantia nigra (SN) and motor dysfunction
It is well established that activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and caspase-1 triggers cleavage of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 leading to their secretion into extracellular space
To examine how IL-10 regulates NLRP3 inflammasome and, affects PD pathogenesis, we stereotaxically injected LPS into the SN of wildtype (WT) and IL-10−/− mice to generate an in vivo PD model

Summary

Introduction

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by progressive loss of dopamine (DA) neurons in the substantia nigra (SN) and motor dysfunction. Emerging evidence has indicated important contributions of chronic neuroinflammation to PD pathogenesis [1,2,3,4,5,6]. How chronic neuroinflammation is formed and maintained remains elusive and warrants further investigation. IL-10 is a pleiotropic regulatory cytokine with both immune-suppressive and immune-stimulatory properties. Beneficial anti-inflammatory effects of IL-10 have been shown in animal models of neurodegenerative diseases, such as Alzheimer’s disease, PD, and multiple sclerosis [7,8,9,10,11,12]. A stimulatory role of IL-10 in antibody production has been found to be associated with the pathogenesis of multiple sclerosis [13]. The precise role and its underlying mechanism of IL-10 in neurodegenerative diseases, including PD, needs further investigation

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