STING promotes homeostatic maintenance of tissues and confers longevity with aging.
STING promotes homeostatic maintenance of tissues and confers longevity with aging.
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STING 促进组织的稳态维持，并随着年龄的增长而延长寿命。
DOI：
10.1101/2024.04.04.588107
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Sharma,Shruti
中科院分区：
文献类型：
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作者：
Hopkins,JacobW;Sulka,KatherineB;Sawden,Machlan;Carroll,KimberlyA;Brown,RonaldD;Bunnell,StephenC;Poltorak,Alexander;Tai,Albert;Reed,EricR;Sharma,Shruti
衰老组织内的局部免疫过程是衰老相关功能障碍的重要驱动因素，但调节这些反应的组织自主途径和细胞类型仍然缺乏表征。通过环GMP-AMP合酶（cGAS）和干扰素基因刺激因子（STING）起作用的细胞溶质DNA传感途径在组织中广泛表达，并且准备调节组织内的局部I型干扰素（IFN-I）依赖性和非依赖性炎症过程。最近的研究表明，cGAS/STING途径可能在加速老化的各种体外和体内模型中驱动病理学。然而，迄今为止，在没有遗传驱动因素的情况下，cGAS/STING途径在生理衰老过程中的作用仍未被探索。这仍然是一个相关的差距，因为STING广泛表达，涉及许多疾病，并且STING的功能丧失多态性在人群中非常普遍（>50%）。在这里，我们揭示，在生理老化，STING缺乏导致小鼠寿命显着缩短，促炎血清细胞因子和组织浸润增加，以及组织学组成和组织的显着变化。我们注意到，老化的心脏，肝脏和肾脏表达不同的炎症，干扰素刺激基因（ISG）和衰老基因的子集，共同构成每个组织的免疫指纹。这些独特的模式在很大程度上是由组织特异性基质和骨髓细胞印记。使用细胞相互作用网络分析，免疫荧光和组织病理学数据，我们表明，这些免疫指纹形状的组织结构和景观的细胞-细胞相互作用在衰老组织。这些与年龄相关的免疫指纹在STING缺乏症中严重失调，在没有STING的情况下，定义老化STING足够组织的关键基因大大减少。免疫特征的变化伴随着基质和骨髓组分的重组，由此细胞：细胞相互作用被严重改变，并导致STING缺陷器官中组织结构的解体。衰老STING缺陷组织中的这种改变的稳态与这些组织中稳态组织驻留巨噬细胞（TRM）群体的跨组织损失相关。离体分析表明，基础STING信号限制TRM的易感性死亡诱导的刺激，并确定其在组织壁龛原位定位，从而促进组织的稳态。总的来说，这些数据颠覆了cGAS/STING信号传导在衰老中主要是病理性的范式，而是表明基础STING信号传导维持组织功能并支持生物体寿命。至关重要的是，我们的研究敦促谨慎地不分青红皂白地靶向这些途径，这可能会导致衰老过程中对健康造成不可预测的病理后果。
Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging. To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (>50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization. We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING-sufficient tissues greatly diminished in the absence of STING. Changes in immune signatures are concomitant with a restructuring of the stromal and myeloid fractions, whereby cell:cell interactions are grossly altered and resulting in disorganization of tissue architecture in STING-deficient organs. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING-signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis. Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.