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Abstract Number: 2098

NRF2 Downregulates Inflammation and Protects Against Autoimmune Lung Disease in Experimental Lupus

Shuhong Han1, Haoyang Zhuang1, Pui Lee2, Lijun Yang3 and Westley Reeves1,4, 1Medicine, University of Florida, Gainesville, FL, 2Harvard Medical School, Boston, MA, 3Pathology, Immunology and laboratory medicine, University of Florida, Gainesville, FL, 4Division of Rheumatology & Clinical Immunology, University of Florida, Gainesville, FL

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Macrophage, ROS and systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, October 23, 2018

Session Title: Systemic Lupus Erythematosus – Animal Models Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: The transcription factor nuclear factor erythroid 2-related factor (Nrf2) is a master regulator of genes involved in cellular defense against oxidative and electrophilic stresses. It forms a cytoplasmic complex with the ubiquitin ligase KEAP1 and CUL3, which in unstressed conditions promote the ubiquitin-mediated degradation of Nrf2. Modification of the reactive cysteine residues of KEAP1 by electrophiles or ROS reduces the ubiquitin ligase activity of KEAP1/CUL3, resulting in Nrf2 stabilization and binding to antioxidant response elements (AREs) in the promoters of target genes. As there is functional cross-talk between Nrf2 and NF-κB mediated inflammatory responses, we hypothesized that Nrf2 might downregulate chronic inflammation in mice with diffuse alveolar hemorrhage (DAH) associated with pristane-induced lupus, a disease driven by macrophages (Mϕ).

Methods: Murine Mϕ subsets were analyzed by flow cytometry and the cell subsets were flow-sorted. Binding of Nrf2 to its target sequence was determined in vitro. Gene expression in sorted Mϕ from pristane or mineral oil (MO) treated mice was determined using RNA-Seq and real-time PCR. Pristane-treated C57BL/6 mice received injections of CDDO-imidazolide every other day, a potent inducer of Nrf2/ARE signaling, or vehicle, starting 3-days after pristane treatment. DAH was assessed on day-14.

Results: Mϕ extracts from pristane-treated B6 mice exhibited lower Nrf2 binding in vitro to AREs vs. extracts from MO-treated controls. RNA-Seq showed that a series of Nrf2-regulated genes involved in the response to oxidative stress were expressed at lower levels in Mϕ from pristane vs. MO-treated mice. Low expression levels were confirmed by real-time PCR and Mϕ from pristane-treated mice had increased mitochondrial superoxide (MitoSox red staining), decreased mitochondrial membrane potential (tetramethylrhodamine staining), and increased cellular ROS (dichlorofluorescein diacetate staining) vs. controls. In vivo injection of CDDO-imidazolide decreased the number of CD11b+Ly6Chi (inflammatory) Mϕ, increased CD11b+CD138+ (pro-resolving) Mϕ, and reversed the pristane-induced changes in mitochondrial superoxide and cellular ROS while restoring mitochondrial membrane potential. Finally, CDDO-imidazolide treatment greatly attenuated the severity of DAH in pristane-treated mice (P<0.0001). A less potent Nrf2 activator, diethylmaleate, also was protective and reduced Mϕ TNFα production.

Conclusion: These observations suggest that oxidative stress is involved in the pathogenesis of chronic inflammation experimental lupus and that pharmacological Nrf2 activation can protect lupus mice from fatal lung hemorrhage.


Disclosure: S. Han, None; H. Zhuang, None; P. Lee, None; L. Yang, None; W. Reeves, None.

To cite this abstract in AMA style:

Han S, Zhuang H, Lee P, Yang L, Reeves W. NRF2 Downregulates Inflammation and Protects Against Autoimmune Lung Disease in Experimental Lupus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/nrf2-downregulates-inflammation-and-protects-against-autoimmune-lung-disease-in-experimental-lupus/. Accessed February 2, 2023.
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