TY - JOUR
T1 - Through reducing ROS production, IL-10 suppresses caspase-1-dependent IL-1β maturation, thereby preventing chronic neuroinflammation and neurodegeneration
AU - Gao, Yun
AU - Tu, Dezhen
AU - Yang, Ru
AU - Chu, Chun Hsien
AU - Gao, Hui Ming
AU - Hong, Jau Shyong
N1 - Funding Information:
This research was funded by the National Natural Science Foundation of China, grant number 31471006 and 21577004; the national high technology research and development program of China, grant number 2014AA021601; the National Basic Research Program of China, grant number 2015BAI08B02; the Fundamental Research Funds for the Central Universities, grant numbers 14913101 and 1480601101; the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the award to high-level innovative and entrepreneurial talents of Jiangsu Province of China to Hui-Ming Gao. This research was funded in part by the Intramural Research Program of the NIH/NIEHS in the United States, grant number ES090082).
Funding Information:
Funding: This research was funded by the National Natural Science Foundation of China, grant number 31471006 and 21577004; the national high technology research and development program of China, grant number 2014AA021601; the National Basic Research Program of China, grant number 2015BAI08B02; the Fundamental Research Funds for the Central Universities, grant numbers 14913101 and 1480601101; the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the award to high-level innovative and entrepreneurial talents of Jiangsu Province of China to Hui-Ming Gao. This research was funded in part by the Intramural Research Program of the NIH/NIEHS in the United States, grant number ES090082).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/1/2
Y1 - 2020/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077942135&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077942135&partnerID=8YFLogxK
U2 - 10.3390/ijms21020465
DO - 10.3390/ijms21020465
M3 - Article
C2 - 31940754
AN - SCOPUS:85077942135
SN - 1661-6596
VL - 21
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 2
M1 - 465
ER -