Laboratoire d'Immunologie, CHU de Toulouse, Institut Fédératif de Biologie, Hôpital Purpan, Toulouse, France.
Institut Toulousain des Maladies Infectieuses et Inflammatoires (INFINITY), INSERM UMR1291, CNRS, Université de Toulouse, Université Paul Sabatier, Toulouse, France.
EBioMedicine. 2022 Jun;80:104047. doi: 10.1016/j.ebiom.2022.104047. Epub 2022 May 10.
Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-α production induced by PRR agonist ligands.
In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-α and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-α.
We observed a female predominance in IFN-α production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-α production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN-α production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-α in response to cGAMP.
We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway.
This work was supported by grants from Région Occitanie/Pyrénées-Méditerranée (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).
浆细胞样树突状细胞（pDC）在病毒感染时会产生 I 型干扰素（IFN-I），这是对 Toll 样受体 7（TLR7）刺激的反应，并且女性比男性更为强烈。这种性别偏向在衰老人群中是否仍然存在目前尚不清楚。在这项研究中，我们研究了性别和衰老对 PRR 激动剂配体诱导 IFN-α 产生的影响。
在一个由 19 岁至 97 岁的个体组成的大队列中，我们测量了全血在 R-848、ODN M362 CpG-C 或 cGAMP 刺激下产生 IFN-α 和炎症细胞因子的情况，这些配体分别激活 TLR7/8、TLR9 或 STING 途径。我们进一步表征了 IFN-α 的细胞来源。
我们观察到，在 TLR7 或 TLR9 配体作用下，pDC 产生 IFN-α 时女性占主导地位。女性 TLR7 驱动的 IFN-α 产生较高，在整个年龄段，包括老年人中，都得到了强有力的维持。TLR9 驱动的干扰素产生的性别偏向在 60 岁后丧失，这与循环 pDC 数量的下降有关。相比之下，STING 驱动的 IFN-α 产生在两性中相似，随着年龄的增长而保持不变，与循环单核细胞数量相关。事实上，单核细胞是 cGAMP 反应中 IFN-α 的主要细胞来源。
我们表明，TLR7 诱导的 IFN-I 产生的性别偏向在很大程度上贯穿整个年龄段，并且确定单核细胞是通过 STING 途径产生 IFN-I 的主要来源。
这项工作得到了奥克西塔尼-比利牛斯地区/地中海地区（#12052910，Inspire 计划#1901175）、保罗·萨巴蒂埃大学和欧洲区域发展基金（MP0022856）的资助。
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