Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice.
Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice.
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DOI：
10.1038/s41598-017-08054-2
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发表时间：
2017-08-18
影响因子：
4.6
通讯作者：
Kashihara N
中科院分区：
文献类型：
--
作者：
Sogawa Y;Nagasu H;Iwase S;Ihoriya C;Itano S;Uchida A;Kidokoro K;Taniguchi S;Takahashi M;Satoh M;Sasaki T;Suzuki T;Yamamoto M;Horng T;Kashihara N
慢性炎症可能是各种器官衰竭的主要驱动因素，包括慢性肾脏疾病(CKD)。在小鼠肾脏疾病模型中，NLRP3(NLRP3)炎性小体在炎症中起关键作用。核因子红系相关因子2(Nrf2)是抗氧化剂反应的主要转录因子，在生理条件下也与炎症体的激活有关。然而，慢性肾脏病中炎性小体激活的机制仍然不清楚。在这里，我们表明，在单侧输尿管梗阻(UUO)的CKD小鼠模型中，Nrf2的缺失可以抑制纤维化和炎症。我们一直观察到炎症相关基因NLRP3和IL-1β在NRF2缺乏的肾脏中的表达减少。巨噬细胞M1而不是M2的渗透增加似乎介导了UUO诱导的CKD症状的抑制。此外，我们还发现，在NRF2缺陷的骨髓来源的巨噬细胞中，NLRP3炎症小体的激活被减弱。这些结果表明，NRF2相关的炎性小体激活可通过M1巨噬细胞的浸润促进CKD症状的发生。因此，我们已经确定Nrf2通路是治疗CKD的一个有前途的靶点。
Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.
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