Mol Cell Biol. 2017 Jul 14;37(15). pii: e00063-17. doi: 10.1128/MCB.00063-17. Print 2017 Aug 1.
Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice.
The transcription factor NRF2 (nuclear factor [erythroid-derived 2]-like 2) plays crucial roles in the defense mechanisms against oxidative stress and mediates anti-inflammatory actions under various pathological conditions. Recent studies showed that the dysfunction of regulatory T cells (Tregs) is directly linked to the initiation and progression of various autoimmune diseases. To determine the Treg-independent impact of NRF2 activation on autoimmune inflammation, we examined scurfy (Sf) mice, which are deficient in Tregs and succumb to severe multiorgan inflammation by 4 weeks of age. We found that systemic activation of NRF2 by Keap1 (Kelch-like ECH-associated protein 1) knockdown ameliorated tissue inflammation and lethality in Sf mice. Activated T cells and their cytokine production were accordingly decreased by Keap1 knockdown. In contrast, NRF2 activation through cell lineage-specific Keap1 disruption (i.e., in T cells, myeloid cells, and dendritic cells) achieved only partial or no improvement in the inflammatory status of Sf mice. Our results indicate that systemic activation of NRF2 suppresses effector T cell activities independently of Tregs and that NRF2 activation in multiple cell lineages appears to be required for sufficient anti-inflammatory effects. This study emphasizes the possible therapeutic application of NRF2 inducers in autoimmune diseases that are accompanied by Treg dysfunction.
KEYWORDS: KEAP1; NRF2; autoimmune diseases; autoimmunity; inflammation
(From pubmed.gov, PMID: 28507037)
Mol Immunol. 2018 Dec 1;105:165-172. doi: 10.1016/j.molimm.2018.11.014. [Epub ahead of print]
Nrf2/ARE pathway inhibits inflammatory infiltration by macrophage in rats with autoimmunemyositis.
Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by muscle disorders. We conducted this study to detect whether NF-E2-related factor 2 (Nrf2) pathway inhibit inflammatory infiltration by macrophage in experimental autoimmune myositis (EAM) rat model.
CD163 levels were examined by immunohistochemistry (IHC), while serum creatine kinase (CK), reactive oxygen species (ROS), and serum monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) levels were determined by enzyme linked immunosorbnent assay (ELISA), both in IIM patients and EAM rat. We also detected MCP-1, TNF-α, IL-6, and Nrf2 levels by Realtime quantitative PCR (RT-PCR) in patients' muscles, and MCP-1, TNF-α, IL-6, and Nrf2, HO-1, NQO-1 levels by RT-PCR and Western blot in EAM rats' muscles. EAM macrophages were separated, and Nrf2 over-expression macrophages were constructed. ROS level and cell migration were detected by flow cytometer and transwell assay respectively. Then, levels of MCP-1, TNF-α, IL-6, Nrf2, Heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase 1 (NQO-1) were detected by RT-PCR and Western blot.
Results showed that EAM rats were histopathologically inflammatory cell infiltration. Levels of CD163, serum CK and ROS, serum/muscle MCP-1, TNF-α and IL-6 increased and muscle Nrf2 level decreased in IIM patients and EAM rats. Cell migration ability and levels of ROS, MCP-1, TNF-α, IL-6, and plasma Nrf2 were down-regulated, and total/nucleus Nrf2, HO-1, NQO-1 were up-regulated notably when Nrf2 over-expressed.
Nrf2 inhibited EAM macrophage infiltration by activating Nrf2/ARE pathway which could induce ROS degradation and inhibit pro-inflammatory factors expression.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Autoimmune myositis; IIM; Inflammatory infiltration; Macrophage; Nrf2/ARE pathway; PM/DM
(From pubmed.gov, PMID: 30513452)
[Notes: Myositis means inflammation of the muscles that you use to move your body. It can be caused by an injury, infection, or autoimmune disease. This December 2018 study shows that this type of autoimmune inflammation can be prevented (inhibited) by activating the Nrf2 pathway.]