RESUMO
For quite a long time, the 11S proteasome activator REGÉ and REGß, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8+ T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8+ T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ-/- kidney. Moreover, REGγ-/- mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.
Assuntos
Envelhecimento/imunologia , Autoantígenos/metabolismo , Doenças Autoimunes/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/metabolismo , Envelhecimento/genética , Animais , Apresentação de Antígeno , Autoantígenos/genética , Doenças Autoimunes/genética , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Camundongos , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/genética , Fator de Transcrição STAT3/metabolismoRESUMO
The integrated wetland systems were constructed by combining horizontal-flow and vertical-flow bed, and their purification efficiencies for septic tank effluent were detected when the hydraulic retention time (HRT) was 1 d, 3 d, 5 d under different seasons. The results showed that the removal efficiencies of the organics, phosphorus were steady in the hybrid systems, but the removal efficiency of total nitrogen was not steady due to high total nitrogen concentration in the septic tank effluent. The average removal rates of COD (chemical oxygen demand) were 89%, 87%, 83%, and 86% in summer, autumn, winter and spring, respectively, and it was up to 88%, 85%, 73%, and 74% for BOD5 (5 d biochemical oxygen demand) removal rate in four seasons. The average removal rates of TP (total phosphorous) could reach up to 97%, 98%, 95%, 98% in four seasons, but the removal rate of TN (total nitrogen) was very low. The results of this study also indicated that the capability of purification was the worst in winter. Cultivating with plants could improve the treated effluent quality from the hybrid systems. The results of the operation of the horizontal-flow and vertical-flow cells (hybrid systems) showed that the removal efficiencies of the organics, TP and TN in horizontal-flow and vertical-flow cells were improved significantly with the extension of HRT under the same season. The removal rate of 3 d HRT was obviously higher than that of 1 d HRT, and the removal rate of 5 d HRT was better than that of 3 d HRT, but the removal efficiency was not very obvious with the increment of HRT. Therefore, 3 d HRT might be recommended in the actual operation of the hybrid systems for economic and technical reasons.
