Early-life inflammation, immune response and ageing
Early-life inflammation, immune response and ageing
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DOI：
10.1098/rspb.2017.0125
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发表时间：
2017-03-15
影响因子：
4.7
通讯作者：
Rolff, Jens
中科院分区：
文献类型：
--
作者：
Khan, Imroze;Agashe, Deepa;Rolff, Jens
炎症相关疾病通常归因于免疫病理学，其导致由不适当的炎症反应引起的自我损伤。与早期炎症相关的免疫病理学似乎也会导致更快的衰老，尽管我们缺乏这种关联的直接实验证据。为了了解衰老、炎症和免疫病理学之间的相互作用，我们使用黄粉虫作为研究生物。我们假设，酚氧化酶，在昆虫防御中的一个重要的免疫效应，可能会造成重大的免疫病理学成本造成组织损伤马氏管（MTs;功能相当于人类肾脏），反过来加速老化。为了支持这一假设，我们发现RNAi敲低年轻人中酚氧化酶（PO）转录物可能减少炎症诱导的对MT的自身反应性组织损伤，并增加成年人的寿命。因此，我们的工作表明，早期炎症的免疫病理学代价与快速衰老之间存在因果关系。我们还推断，如果自然选择随着年龄的增长而减弱，那么老年人应该表现出与免疫应答相关的免疫病理学成本增加。事实上，我们发现，虽然老年感染者比年轻人更快地清除感染，但他们也可能表现出更严重的免疫病理学代价（MT功能下降更大）和更高的感染后死亡率。RNAi介导的PO反应敲低部分挽救了老年甲虫中的MT功能，并导致感染后寿命延长。两者合计，我们的数据是一致的，在昆虫衰老过程中的免疫反应的免疫病理学后果的直接作用。我们的工作也是第一份强调组织损伤在衰老和免疫反应的不同背景下的普遍作用的报告。
Age-related diseases are often attributed to immunopathology, which results in self-damage caused by an inappropriate inflammatory response. Immunopathology associated with early-life inflammation also appears to cause faster ageing, although we lack direct experimental evidence for this association. To understand the interactions between ageing, inflammation and immunopathology, we used the mealworm beetle Tenebrio molitor as a study organism. We hypothesized that phenoloxidase, an important immune effector in insect defence, may impose substantial immunopathological costs by causing tissue damage to Malpighian tubules (MTs; functionally equivalent to the human kidney), in turn accelerating ageing. In support of this hypothesis, we found that RNAi knockdown of phenoloxidase (PO) transcripts in young adults possibly reduced inflammation-induced autoreactive tissue damage to MTs, and increased adult lifespan. Our work thus suggests a causative link between immunopathological costs of early-life inflammation and faster ageing. We also reasoned that if natural selection weakens with age, older individuals should display increased immunopathological costs associated with an immune response. Indeed, we found that while old infected individuals cleared infection faster than young individuals, possibly they also displayed exacerbated immunopathological costs (larger decline in MT function) and higher post-infection mortality. RNAi-mediated knockdown of PO response partially rescued MTs function in older beetles and resulted in increased lifespan after infection. Taken together, our data are consistent with a direct role of immunopathological consequences of immune response during ageing in insects. Our work is also the first report that highlights the pervasive role of tissue damage under diverse contexts of ageing and immune response.