S-propargyl-cysteine attenuates inflammatory response in rheumatoid arthritis by modulating the Nrf2-ARE signaling pathway

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Hydrogen sulfide (H2S), the third physiological gasotransmitter, is well recognized as an anti-inflammatory mediator in various inflammatory conditions. Herein, we explored the protective effects of S-propargyl-cysteine (SPRC, also known as ZYZ-802), an endogenous H2S modulator, on RA and determined the underlying mechanisms. In the present study, SPRC concentration-dependently attenuated inflammatory mediator expression, reactive oxidase species generation, and the expression and activity of matrix metalloproteinases (MMP)-9 in interleukin (IL)-1β-induced human rheumatoid fibroblast-like synoviocytes MH7A. In addition, SPRC blocked IL-1β-mediated migration and invasion of MH7A cells. As expected, the protective effects of SPRC were partially abrogated by DL-propargylglycine (PAG, a H2S biosynthesis inhibitor). In vivo study also demonstrated that SPRC treatment markedly ameliorated the severity of RA in adjuvant-induced arthritis rats, and this effect was associated with the inhibition of inflammatory response. We further identified that SPRC remarkably induced heme oxygenase-1 expression associated with the degradation of Kelch-like ECH-associated protein 1 (Keap1) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); this effect was attributed to the sulfhydrylation of the cysteine residue of Keap1. Our data demonstrated for the first time that SPRC, an endogenous H2S modulator, exerted anti-inflammatory properties in RA by upregulating the Nrf2-antioxidant response element (ARE) signaling pathway.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Deletion of the NRF2 gene increases vulnerability to joint alterations in experimental RA models. For instance, in mice expressing the T cell receptor KRN and the major histocompatibility complex class II molecule A(g7) (the K/BÂN arthritis model), and in antibody-induced arthritis, NRF2 deficiency accelerates the incidence and aggravates the disease course (Maicas et al, 2011;Wu et al, 2016b). NRF2 deficiency dramatically upregulates migration of inflammatory cells, expression of cyclooxygenase-2 and inducible nitric oxide synthase, production of ROS and RNS, and release of proinflammatory cytokines and chemokines.…”

“…NRF2 deficiency dramatically upregulates migration of inflammatory cells, expression of cyclooxygenase-2 and inducible nitric oxide synthase, production of ROS and RNS, and release of proinflammatory cytokines and chemokines. Moreover, NRF2 may be a protective factor for bone metabolism in arthritis (Maicas et al, 2011), and NRF2/HO-1 activation exerts anti-inflammatory and antioxidant effects in animal models of RA and in human synovial fibroblasts (Wu et al, 2016b). It is interesting that antirheumatic gold(I)-containing compounds that stimulate the antioxidant response through activation of NRF2 and upregulation of HO-1 and GCLC proved clinical efficacy in RA .…”

“…It is interesting that antirheumatic gold(I)-containing compounds that stimulate the antioxidant response through activation of NRF2 and upregulation of HO-1 and GCLC proved clinical efficacy in RA . Moreover, NRF2/HO-1 activation mediates the induction of synovial cell apoptosis and inhibition of proinflammatory cytokine production by cilostazol (Park et al, 2010) as well as the anti-inflammatory effects of H 2 S and related compounds, which are able to modify by sulfhydration the cysteine residues of KEAP1 (Wu et al, 2016b). Other drugs that induce NRF2 and HO-1 signaling, such as rebamipide, can divert the differentiation of human and murine CD4 + T cells toward an immunosuppressive Treg phenotype and inhibit the differentiation of TCD4 + cells toward inflammatory Th17 cells through specific inhibition of STAT3 (Moon et al, 2014).…”

“…Excessive ROS generation within the inflamed synovium appears to contribute to the pathogenesis of RA because patients show a marked increase in ROS formation, lipid peroxidation, protein oxidation, DNA damage, and decrease in the activity of the antioxidant defense mechanisms, all of these contributing to tissue damage and disease progression (Datta et al, 2014). In response to pathologic ROS formation, the NRF2 pathway is activated in synovial cells of RA patients and in joints of antibody-induced arthritic mice, but this response is apparently insufficient to counteract the disease progression (Wu et al, 2016b).…”

Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors

“…Hydrogen sulfide (comprising H 2 S and HS − ) is the third endogenous gasotransmitter alongside NO and carbon monoxide and acts as a signalling molecule across numerous physiological systems (Kimura, 2014;Szabo et al, 2014). Given exogenously in preclinical studies, sulfide protected against diverse pathological conditions, ranging from circulatory (Wang, Wang, Guo, & Zhu, 2011), neurodegenerative (Zhang & Bian, 2014) and arthritic (Wu et al, 2016) disorders to diabetes (Wu et al, 2009), pain (Di Cesare Mannelli et al, 2017), and cancer (Lee et al, 2014). Our particular interest in sulfide relates to its ability to transiently reduce cellular respiration by inhibition of mitochondrial cytochrome C oxidase (Szabo et al, 2014).…”