Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.
Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women.
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DOI：
10.4049/jimmunol.1501684
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发表时间：
2015-12-01
期刊：
影响因子：
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通讯作者：
Altfeld M
中科院分区：
文献类型：
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作者：
Griesbeck M;Ziegler S;Laffont S;Smith N;Chauveau L;Tomezsko P;Sharei A;Kourjian G;Porichis F;Hart M;Palmer CD;Sirignano M;Beisel C;Hildebrandt H;Cénac C;Villani AC;Diefenbach TJ;Le Gall S;Schwartz O;Herbeuval JP;Autran B;Guéry JC;Chang JJ;Altfeld M
IFNα产生的增加有助于感染性和自身免疫性疾病的发病机制。女性浆细胞样树突状细胞（pDC）在TLR7刺激下比男性pDC产生更多的IFNα，但这种差异的机制仍不清楚。在这里，我们发现，基础水平的干扰素调节因子5（IRF5）在pDC中显着高于女性相比，男性和正相关的IFNα分泌的pDC的百分比。将重组IRF5蛋白递送到人原代pDC中增加TLR7介导的IFNα分泌。在小鼠中，造血区室或DC谱系中雌激素受体1（Esr 1）基因的基因切除减少了pDC中IRF 5 mRNA的表达和IFNα的产生。此外，IRF5 mRNA水平与人pDC中的Esr1 mRNA水平相关，这与Esr1在转录水平上对IRF5的调节一致。综上所述，这些数据证明了一种关键机制，通过该机制，基础pDC IRF5表达的性别差异导致女性在TLR7刺激后产生更高的IFNα，并为调节免疫应答和炎症提供了新的靶标。
Increased IFNα production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFNα upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. Here, we show that basal levels of interferon regulatory factor 5 (IRF5) in pDCs were significantly higher in females compared to males and positively correlated with the percentage of IFNα-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFNα secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced IRF5 mRNA expression in pDCs and IFNα production. IRF5 mRNA levels furthermore correlated with Esr1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by Esr1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFNα production upon TLR7 stimulation in females, and provide novel targets for the modulation of immune responses and inflammation.