4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

Zhang, Qingchen; Bai, Xiaohui; Wang, Rongrong; Zhao, Hao; Wang, Lili; Li, Jingwen; Li, Ming; Chen, Zheng; Wang, Zejun; Li, Lianxin; Wang, Dawei

doi:10.1111/jcmm.17185

Cited by 27 publications

(19 citation statements)

References 55 publications

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“…Another study also showed that 4-OI significantly inhibited ROS production by activating Nrf2, which in turn caused downregulation of AMPK phosphorylation levels, and improved free fatty acid-induced oxidative stress and lipid metabolism disorders in hepatocytes [ 43 ]. Itaconate has also attenuated inflammatory damage through activation of Nrf2 in other diseases such as osteoarthritis [ 44 – 47 ], nerve injury [ 48 , 49 ], cardiovascular disease [ 50 , 51 ], systemic lupus erythematosus [ 52 ], vitiligo [ 53 ], periodontitis [ 54 ], fungal keratitis [ 55 ], and diabetic wound repair [ 56 ]. Consequently, itaconate, as an Nrf2 agonist, may present new therapeutic opportunities for many inflammatory diseases.…”

Section: Immunomodulatory Mechanisms Of Itaconatementioning

confidence: 99%

Itaconate: A Potent Macrophage Immunomodulator

Zheng

Kong

et al. 2023

Inflammation

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With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.

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Section: Immunomodulatory Mechanisms Of Itaconatementioning

confidence: 99%

Itaconate: A Potent Macrophage Immunomodulator

Zheng

Kong

et al. 2023

Inflammation

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“…OI and DMF have protective effects on the cartilage in OA. More specifically, OI-induced transcription of Nrf2 in chondrocytes results in the high expression of HO-1, NQO1, and GCLC, and the low secretion of IL-6, IL-10, MCP-1, and TNF-a, which can switch the prevention from cell death and apoptosis of chondrocytes via decreasing oxidative stress and inflammation responses, and put a brake on the progress of OA in vivo (224,225). Similarly, dimethyl fumarate (DMF) can suppress the production of MMP-1, MMP-3, and MMP-13 and the destruction of COL2 induced by TNF-a in OA, which appears to work by inhibiting JAK/STAT3 signaling (226).…”

Section: Potential Treatment Strategies For Oa Linking Nrf2 Activatio...mentioning

confidence: 99%

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

Wang

2022

Front. Immunol.

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Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.

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“…Because itaconate could activate NRF2, OI has also been shown to play an antioxidant role to improve the cell survival 20 . For example, OI could improve the LPS‐induced chondrocyte inflammation and attenuate the H2O2‐induced neuronal reactive oxygen species (ROS) generation and lipid oxidation 25,26 . Furthermore, OI could also improve the prognosis in prebrain/liver ischemia–reperfusion injury and inhibit UVB‐induced oxidative stress in melanocytes and keratinocytes 27–29 .…”

Section: Introductionmentioning

confidence: 99%

“…20 For example, OI could improve the LPS-induced chondrocyte inflammation and attenuate the H2O2-induced neuronal reactive oxygen species (ROS) generation and lipid oxidation. 25,26 Furthermore, OI could also improve the prognosis in prebrain/ liver ischemia-reperfusion injury and inhibit UVB-induced oxidative stress in melanocytes and keratinocytes. [27][28][29] These studies have revealed the sound antioxidant effects and protection of OI.…”

mentioning

confidence: 99%

4‐octyl itaconate improves the viability of D66H cells by regulating the KEAP1‐NRF2‐GCLC/HO‐1 pathway

Chen

Wang

Song

et al. 2023

J Cellular Molecular Medi

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As a rare and refractory hereditary skin disease belonging to the familial and autosomal dominant dermatosis, the Vohwinkel syndrome (VS) is characterized by diffuse hyperkeratosis in the palms of hands and soles of feet, which would develop to auto-amputation if not treated adequately. 1,2 This disease is usually accompanied by many other medical disorders, for example sensorineural deafness, ichthyosis, vitiligo and mental retardation, severely affecting the patients' physical and mental health. 2 However, the effective therapeutic treatment of VS is still lacking in the clinical settings. 3 Recent studies have shown that there are two types of palmoplantar keratoderma mutilating. One is an ichthyosis-related variant caused by the insertional mutations in the loricrin gene. [4][5][6] The other

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4‐octyl Itaconate inhibits lipopolysaccharide (LPS)‐induced osteoarthritis via activating Nrf2 signalling pathway

Cited by 27 publications

References 55 publications

Itaconate: A Potent Macrophage Immunomodulator

Itaconate: A Potent Macrophage Immunomodulator

Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

4‐octyl itaconate improves the viability of D66H cells by regulating the KEAP1‐NRF2‐GCLC/HO‐1 pathway

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