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LXR signaling controls homeostatic dendritic cell maturation
Science Immunology ( IF 24.8 ) Pub Date : 2023-05-12 , DOI: 10.1126/sciimmunol.add3955
Victor Bosteels 1, 2 , Sandra Maréchal 1, 2 , Clint De Nolf 1, 2, 3, 4 , Sofie Rennen 1, 2 , Jonathan Maelfait 3, 5 , Simon J Tavernier 3, 6, 7 , Jessica Vetters 1, 2 , Evelien Van De Velde 1, 2 , Farzaneh Fayazpour 1, 2 , Kim Deswarte 2, 8 , Alexander Lamoot 9 , Julie Van Duyse 3, 10 , Liesbet Martens 3, 11, 12 , Cédric Bosteels 2, 8 , Ria Roelandt 13, 14 , Annelies Emmaneel 13, 15 , Sofie Van Gassen 13, 15 , Louis Boon 16 , Gert Van Isterdael 3, 10 , Isabelle Guillas 17 , Niels Vandamme 13, 14 , Doris Höglinger 18 , Bruno G De Geest 9 , Wilfried Le Goff 17 , Yvan Saeys 13, 15 , Kodi S Ravichandran 3, 19, 20 , Bart N Lambrecht 2, 8, 21 , Sophie Janssens 1, 2
Affiliation  

Dendritic cells (DCs) mature in an immunogenic or tolerogenic manner depending on the context in which an antigen is perceived, preserving the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well-characterized, the signals that drive tolerogenic maturation during homeostasis are still poorly understood. We found that the engulfment of apoptotic cells triggered homeostatic maturation of type 1 conventional DCs (cDC1s) within the spleen. This maturation process could be mimicked by engulfment of empty, nonadjuvanted lipid nanoparticles (LNPs), was marked by intracellular accumulation of cholesterol, and was highly specific to cDC1s. Engulfment of either apoptotic cells or cholesterol-rich LNPs led to the activation of the liver X receptor (LXR) pathway, which promotes the efflux of cellular cholesterol, and repressed genes associated with immunogenic maturation. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs repressed the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell–mediated immunity. These data demonstrate that conserved cellular cholesterol efflux pathways are differentially regulated in tolerogenic versus immunogenic cDC1s and suggest that administration of nonadjuvanted cholesterol-rich LNPs may be an approach for inducing tolerogenic DC maturation.

中文翻译:

LXR 信号控制稳态树突状细胞成熟

树突状细胞 (DC) 以免疫原性或致耐受性方式成熟,具体取决于感知抗原的环境,从而保持免疫和耐受之间的平衡。尽管响应感染性损伤而驱动免疫原性成熟的途径已得到充分表征,但在体内平衡期间驱动致耐受性成熟的信号仍知之甚少。我们发现凋亡细胞的吞噬触发了脾脏内 1 型常规 DC (cDC1s) 的稳态成熟。这种成熟过程可以通过空的、无佐剂的脂质纳米颗粒 (LNP) 的吞噬来模拟,其特征是细胞内胆固醇的积累,并且对 cDC1 具有高度特异性。凋亡细胞或富含胆固醇的 LNP 的吞噬导致肝脏 X 受体 (LXR) 通路的激活,它促进细胞胆固醇的流出,并抑制与免疫原性成熟相关的基因。相比之下,TLR3 通过施用聚 (I:C) 佐剂 LNP 同时参与模拟病毒感染会抑制 LXR 通路,从而延迟细胞胆固醇流出并诱导促进 T 细胞介导免疫的基因。这些数据表明,保守的细胞胆固醇流出途径在致耐受性和免疫原性 cDC1 中受到不同的调节,并表明给予非佐剂的富含胆固醇的 LNP 可能是诱导致耐受性 DC 成熟的一种方法。C)-佐剂化的 LNP 抑制 LXR 通路,从而延迟细胞胆固醇流出并诱导促进 T 细胞介导的免疫的基因。这些数据表明,保守的细胞胆固醇流出途径在致耐受性和免疫原性 cDC1 中受到不同的调节,并表明给予非佐剂的富含胆固醇的 LNP 可能是诱导致耐受性 DC 成熟的一种方法。C)-佐剂化的 LNP 抑制 LXR 通路,从而延迟细胞胆固醇流出并诱导促进 T 细胞介导的免疫的基因。这些数据表明,保守的细胞胆固醇流出途径在致耐受性和免疫原性 cDC1 中受到不同的调节,并表明给予非佐剂的富含胆固醇的 LNP 可能是诱导致耐受性 DC 成熟的一种方法。
更新日期:2023-05-12
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