Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Yuji Sogawa,Seiji Itano,Masafumi Takahashi,Takafumi Suzuki,Kengo Kidokoro,Atsushi Uchida,Masayuki Yamamoto,Shun’Ichiro Taniguchi,Minoru Satoh,Shigeki Iwase,Chieko Ihoriya,Naoki Kashihara,Hajime Nagasu,Tiffany Horng,Tamaki Sasaki

doi:10.1038/s41598-017-08054-2

Abstract

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.

Highlights

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor for anti-oxidant and detoxification responses[1, 2]
We focused on the role of Nrf[2] in macrophages in kidney disease because the number of infiltrated macrophages decreased in the Nrf2-KO mice compared with the WT mice by Day 14 after ureter obstruction (UUO) (Supplementary Fig. S1)
Nrf2-related NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation was important for maintaining the M1 population in this disease model and, as a result, seems to contribute to the process by which organ inflammation becomes chronic inflammation

Summary

Introduction

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor for anti-oxidant and detoxification responses[1, 2]. Nrf[2] knockout has led to the amelioration of several metabolic disorders and cardiovascular diseases, including atherosclerosis[17,18,19,20,21], obesity[22], and type 2 diabetes[23], all of which are typically associated with chronic inflammation. These observations raise the intriguing possibility that Nrf[2] may affect kidney diseases via inflammasome activation in addition to, or in lieu of, its classic role as an oxidative stress response factor. These data increase our understanding of the role of Nrf[2] in kidney diseases

Methods

Results

Conclusion