Aging-related, nonresolving inflammation in both the central nervous system (CNS) and periphery predisposes individuals to the development of neurodegenerative disorders (NDDs). Inflammasomes are thought to be especially relevant to immune homeostasis, and their dysregulation contributes to inflammation and NDDs. However, few agents have been clinically shown to reduce NDD incidence by targeting inflammasomes. Our study indicated that NLRP3 (NLR family, pyrin domain containing 3) inflammasome is involved in Parkinson disease (PD) progression in patients and various murine models. In addition, the small molecule kaempferol (Ka) protected mice against LPS-and SNCA-induced neurodegeneration by inhibiting NLRP3 inflammasome activation as evidenced by the fact that Ka reduced cleaved CASP1 expression and disrupted NLRP3-PYCARD-CASP1 complex assembly with concomitant decreased IL1B secretion. Mechanically, Ka promoted macroautophagy/autophagy in microglia, leading to reduced NLRP3 protein expression, which in turn deactivated the NLRP3 inflammasome. Intriguingly, ubiquitination was involved in Ka-induced autophagic NLRP3 degradation. These findings were further confirmed in vivo as knockdown of Atg5 expression or autophagy inhibitor treatment significantly inhibited the Ka-mediated NLRP3 inflammasome inhibition and neurodegeneration amelioration. Thus, we demonstrated that Ka promotes neuroinflammatory inhibition via the cooperation of ubiquitination and autophagy, suggesting that Ka is a promising therapeutic strategy for the treatment of NDDs.
Astrocytes are involved in the neuroinflammation of neurodegenerative diseases, such as Parkinson's disease (PD). Among the numerous inflammatory cytokines, interleukin-1β (IL-1β) produced by astrocytic Nod-like receptor protein (NLRP) inflammasome is crucial in the pathogenesis of PD. β-arrestin2-mediated dopamine D2 receptor (Drd2) signal transduction has been regarded as a potential anti-inflammatory target. Our previous study revealed that astrocytic Drd2 suppresses neuroinflammation in the central nervous system. However, the role of Drd2 in astrocytic NLRP3 inflammasome activation and subsequent IL-1β production remains unclear. In the present study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model to investigate whether Drd2 could suppress astrocytic NLRP3 inflammasome activation. We showed that Drd2 agonist inhibited NLRP3 inflammasome activation, evidenced by decreased caspase-1 expression and reduced IL-1β release in the midbrain of wild type mice. The anti-inflammasome effect of Drd2 was abolished in β-arrestin2 knockout and β-arrestin2 small interfering RNA-injected mice, suggesting a critical role of β-arrestin2 in Drd2-regulated NLRP3 inflammasome activation. We also found that Drd2 agonists suppressed the upregulation of caspase-1 and IL-1β expression in primary cultured mouse astrocytes in response to the activation of NLRP3 inflammasome induced by lipopolysaccharide plus adenosine triphosphate. Furthermore, we demonstrated that β-arrestin2 mediated the inhibitory effect of Drd2 on NLRP3 inflammasome activation via interacting with NLRP3 and interfering the inflammasome assembly. Collectively, our study illustrates that astrocytic Drd2 inhibits NLRP3 inflammasome activation through a β-arrestin2-dependent mechanism, and provides a new strategy for treatment of PD.
Abstract. Long-term continuous measurements of total gaseous mercury (TGM=gaseous elemental mercury (GEM)+ reactive gaseous mercury (RGM)) were conducted simultaneously along with meteorological variables and a suite of trace gases at an urban site in Nanjing, China from 18 January to 31 December 2011. Measurements were conducted using a high resolution mercury vapor analyzer (Tekran 2537B) with 5-min time resolution. The average concentration of TGM was 7.9 ± 7.0 ng m −3 with a range of 0.8-180 ng m −3 over the study period. TGM concentrations followed a typical lognormal pattern dominated by a range of 3-7 ng m −3 , which was significantly higher than the continental background values (∼1.5 ng m −3 ) in Northern Hemisphere. The mean seasonal TGM concentrations decreased in the following order: summer, spring, fall, and winter. This seasonal pattern was quite different from measurements at most other sites around the world. We attributed high monthly average concentrations to the re-volatilization of deposited mercury during the warm season due to high temperatures and greater solar radiation. Previous modeling studies suggested that Nanjing and the surrounding region have the largest Chinese natural emissions during the summer. Positive correlations between temperature, solar radiation, and TGM concentration combined with no correlation between CO and TGM in summer provide a strong indication that natural sources are important in Nanjing while most sharp peaks were caused by anthropogenic sources. TGM concentrations in Nanjing exhibited a noticeable diurnal pattern with a sharp increase after sunrise and peak of greater than 8 ng m −3 during 7-10 a.m. local time. Further, seasonally averaged diurnal cycles of TGM exhibited considerably different patterns with the largest variation in spring and insignificant fluctuations in winter. Using HYSPLIT backwards trajectories from six clusters, it was indicated that the highest TGM concentrations, 11.9 ng m −3 , was derived from local air masses. The cleanest air masses, with an average TGM concentration of 4.7 and 5.9 ng m −3 , were advected from the north via fast transport facilitated by sweeping synoptic flows.
An online coupled regional climate-chemistry model called RegCCMS is used to investigate the interactions between anthropogenic aerosols and the East Asian summer monsoon (EASM) over East Asia. The simulation results show that the mean aerosol loading and optical depth over the region are 17.87 mg/m 2 and 0.25, respectively. Sulfate and black carbon (BC) account for approximately 61.2% and 7.8% of the total aerosols, respectively. The regional mean radiative forcing (RF) is approximately À3.64, À0.55, and +0.88 W/m 2 at the top of the atmosphere for the total aerosol effect, the total aerosol direct effect, and the BC direct effect, respectively. The surface direct RF of BC accounts for approximately 31% of the total RF of all aerosols. Because of the total aerosol effect, both the energy budgets and air temperature are considerably reduced in the region with high aerosol loadings, leading to decreases in the land-ocean air temperature gradient in summer. The total column-absorbed solar radiation and surface air temperature decrease by 8.4 W/m 2 and 0.31 K,respectively. This cooling effect weakens horizontal and vertical atmospheric circulations over East Asia.The wind speed at 850 hPa decreases by 0.18 m/s, and the precipitation decreases by 0.29 mm/d. The small responses of solar radiation, air temperature, and atmospheric circulations to the BC warming effect are opposite to those of the total aerosol effect. The BC-induced enhancement of atmospheric circulation can increase local floods in south China, while droughts in north China may worsen in response to the BC semidirect effect. The total aerosol effect is much more significant than the BC direct effect. The East Asian summer monsoon becomes weaker due to the total aerosol effect. However, this weakness could be partially offset by the BC warming effect. Sensitivity analyses further indicate that the influence of aerosols on the EASM might be more substantial in years when the southerlies or southwesterlies at 850 hPa are weak compared with years when the winds are strong. Changes in the EASM can induce variations in the distribution and magnitude of aerosols. Aerosols in the lower troposphere over the region can increase by 3.07 and 1.04 μg/m 3 due to the total aerosol effect and the BC warming effect, respectively.
Organic nucleation is an important source of atmospheric aerosol number concentration, especially in pristine continental regions and during the preindustrial period. Here, we improve on previous simulations that overestimate boundary layer nucleation in the tropics and add changes to climate and land use to evaluate climate forcing. Our model includes both pure organic nucleation and heteromolecular nucleation of sulfuric acid and organics and reproduces the profile of aerosol number concentration measured in the Amazon. Organic nucleation decreases the sum of the total aerosol direct and indirect radiative forcing by 12.5%. The addition of climate and land use change decreases the direct radiative forcing (−0.38 W m−2) by 6.3% and the indirect radiative forcing (−1.68 W m−2) by 3.5% due to the size distribution and number concentration change of secondary organic aerosol and sulfate. Overall, the total radiative forcing associated with anthropogenic aerosols is decreased by 16%.
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