最新研究表明：阳光照射和肾损伤存在联系

编辑翻译：奇奇

译文校对：菁菁

文献于2021年1月首次发表在最新的《美国国家科学院院刊》（Proceedings of the National Academy of Sciences）。文献中达特茅斯盖泽尔医学院和华盛顿大学(UW)的研究人员共同揭示了紫外线照射与肾损伤之间的联系。

达特茅斯盖泽尔医学院和华盛顿大学(UW)的研究人员进行了一项新的合作研究，并将研究成果发表在《美国国家科学院院刊》(PNAS)上，该研究揭示了皮肤暴露在紫外线下会如何加剧狼疮等自身免疫性疾病的临床症状。

狼疮是一种自身免疫性疾病，可导致免疫系统攻击自身组织，从而引起关节、皮肤、肾脏、血细胞、脑部、心脏和肺部的炎症。

先前的研究已经证实，多达80%的狼疮患者中，阳光照射会引发他们局部皮肤炎症和全身炎症的恶化，包括肾脏疾病。但人们对推动这一过程的潜在机制知之甚少。

为了确定紫外线是如何引发肾脏炎症的，研究小组研究了中性粒细胞的作用。中性粒细胞是一种白细胞，在人体中大量存在。对于任何类型的炎症，它都是最先反应的免疫细胞，且被认为与狼疮患者的皮肤和肾脏组织损伤有关。

在这项研究中，研究人员对小鼠进行紫外线照射，并在照射的不同时间点寻找皮肤、血液和肾脏中炎症和损伤的标志物。他们能够证明中性粒细胞不仅浸润到紫外线照射下的皮肤，且分散在整个循环系统，从而迁移到肾脏。

Sladjana Skopelja-Gardner博士是盖塞尔大学医学助理教授，她与华盛顿大学医学博士Keith Elkon合作进行了该项研究。她提到：“我们认为这些中性粒细胞中有一个亚群更具破坏性。它们首先进入暴露于紫外线的皮肤，然后转身进入肾脏。这种情况有点不寻常。我们通常认为中性粒细胞是短命的细胞，它会快速到达炎症所在的位置，然后在那里死亡。”

研究人员发现，即使是正常的健康小鼠，皮肤单次暴露在紫外线下也会刺激肾脏的炎症和损伤过程，包括出现短暂性蛋白尿。

Skopelja-Gardner解释说：“需要明确的是，正常健康的小鼠不会患上在狼疮患者中常见的临床类型肾脏疾病，而是出现了我们所说的亚临床损伤，这意味着肾脏发生了无法通过病理学检查或组织检查发现的炎症和损伤过程。之后，小鼠就恢复了健康。”

她补充说道：“但是，这种亚临床损伤可能导致狼疮患者易患炎症的病理后果，这种病理后果就是在暴露于阳光下时会导致肾脏疾病发作。”

重要的是，研究人员在经过紫外线照射后的小鼠肾脏中检测到了炎症和损伤标志物，这标志物与狼疮患者中重症肾脏损害相关的标志物非常相似。此外，暴露于紫外线下也触发了免疫反应，这种免疫反应通常出现在大多数狼疮患者的皮肤和肾脏中，即1型干扰素反应。

Skopelja-Gardner说：“总之，我认为我们的研究表明，皮肤暴露在紫外线下可能是与狼疮相关炎症的通路来源。而在导致肾损伤的过程中，中性粒细胞作为致病的炎症介质扮演了关键角色。”

英文原文

Study Reveals New Insights into the Link Between Sunlight Exposure and Kidney Damage

A new collaborative study from researchers at the Geisel School of Medicine at Dartmouth and the University of Washington (UW) and published in the Proceedings of the National Academy of Sciences (PNAS), reveals unexpected insights into how skin exposure to ultraviolet (UV) light can worsen clinical symptoms in autoimmune diseases such as lupus.

Lupus, an autoimmune disease that can cause inflammation of the joints, skin, kidneys, blood cells, brain, heart and lungs, is caused when the immune system attacks its own tissue.

Previous research has established that in up to 80 percent of lupus patients, sunlight exposure can trigger both local skin inflammation and systemic flares, including kidney disease. But little has been understood about the underlying mechanisms that drive this process.

To define how UV light triggers kidney inflammation, the research team investigated the role of neutrophils—a type of white blood cell abundantly found in the body that acts as a first responder to any kind of inflammation and has been linked to skin and kidney tissue injury in lupus patients.

In the study, the researchers looked for markers of inflammation and injury in the skin, the blood, and the kidney at different time points following UV light exposure in mice. They were able to demonstrate that neutrophils not only infiltrated the UV light-exposed skin, but also dispersed throughout the circulatory system and migrated to the kidney.

"Interestingly, one subset of these neutrophils, the ones that we think are more damaging, first went to the skin that was exposed to the UV light and then turned around and went to the kidney," says Sladjana Skopelja-Gardner, Ph.D., an assistant professor of medicine at Geisel who worked with Keith Elkon, MD, at UW on the study. "That's a bit unusual—we normally think of neutrophils as short-lived cells that sort of zoom to where the inflammation is and then die off there."

The investigators found that a single exposure of skin to UV light stimulates inflammatory and injury processes in the kidney, including transient proteinuria, even in normal, healthy mice.

"To be clear, normal, healthy mice don't get the clinical type of kidney disease that you see in lupus patients," explains Skopelja-Gardner. "They get what we call subclinical injury, meaning there is an inflammatory and injury process happening in the kidney that is not visible by pathology or looking at the tissue itself. The mice recover and are fine afterwards.

"However," she adds, "this subclinical injury may lead to pathologic consequences in the vulnerable setting of pre-existing inflammation in lupus patients, and lead to kidney disease flare after exposure to sunlight."

Importantly, the inflammatory and injury markers they detected in the mouse kidneys following UV light exposure were very similar to the renal injury markers that are associated with more severe kidney damage in lupus patients. In addition, the exposure to UV light also triggered an immune response that is often expressed in most lupus patients—the type 1 interferon response—in both the skin and kidney.

"Overall, I think what our research demonstrates is that skin exposure to UV light can be the source of inflammatory pathways that are relevant to lupus, and that neutrophils play an important role as a pathogenic mediator in this process, contributing to kidney damage." says Skopelja-Gardner.

参考文献：

Sladjana Skopelja-Gardner et al, Acute skin exposure to ultraviolet light triggers neutrophil-mediated kidney inflammation, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2019097118

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