ROS inhibition increases KDM6A-mediated NOX2 transcription and promotes macrophages oxidative stress and M1 polarization

Zhao, Yunxi; Wang, Luyang; Liu, Mingwei; Du, Anning; Qiu, Ming; Shu, Huanyu; Li, Lü; Kong, Xiangqing; Sun, Wei

doi:10.1007/s12192-023-01347-8

Cited by 4 publications

(3 citation statements)

References 35 publications

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“…Due to this phenomenon, we analyzed ROS, nitrite (oxidation product of NO) and TNF-α production in IFN-γ-induced RAW264.7 cells following KRP-6 treatment (Figure 5B,C). Knowingly, antioxidants affect inflammatory macrophage activation by eliminating ROS and thereby lowering nitrite and TNF-α production [94]. Our present results, however, overruled this possibility (Figure 5A) and concluded that KRP-6, the selective MIF ketonase inhibitor, effectively inhibits ROS production, a of M1 macrophage polarization without a radical scavenging effect.…”

Section: Discussioncontrasting

confidence: 46%

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Vámos,

Kálmán,

Sturm

et al. 2023

Antioxidants

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Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production and acceleration of glycolysis. Macrophage migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase and enolase), was discovered to regulate M1 polarization. Here, we reveal that KRP-6, a potent and highly selective MIF ketonase inhibitor, reduces MIF-induced human blood eosinophil and neutrophil migration similarly to ISO-1, the most investigated tautomerase inhibitor. We equally discovered that KRP-6 prevents M1 macrophage polarization and reduces ROS production in IFN-γ-treated cells. During metabolic reprogramming, KRP-6 improved mitochondrial bioenergetics by ameliorating basal respiration, ATP production, coupling efficiency and maximal respiration in LPS+IFN-γ-treated cells. KRP-6 also reduced glycolytic flux in M1 macrophages. Moreover, the selective MIF ketonase inhibitor attenuated LPS+IFN-γ-induced downregulation of PARP-1 and PARP-2 mRNA expression. We conclude that KRP-6 represents a promising novel therapeutic compound for autoimmune diseases, which strongly involves M1 macrophage polarization.

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Section: Discussioncontrasting

confidence: 46%

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Vámos,

Kálmán,

Sturm

et al. 2023

Antioxidants

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“…This process results in upregulating pro-inflammatory factors such as TNF-α and IL-1β. 65 – 67 Moreover, studies have demonstrated significantly elevated levels of inflammatory cytokines, including IL-1β and TNF-α, in joint fluid compared to healthy controls in OA. 64 Our study revealed that compared with the M1 macrophage co-cultured with DPSCs or RDGel, those co-cultured with DPSCs/RDGel had significantly lower intracellular ROS.…”

Section: Discussionmentioning

confidence: 99%

Delivery of dental pulp stem cells by an injectable ROS-responsive hydrogel promotes temporomandibular joint cartilage repair via enhancing anti-apoptosis and regulating microenvironment

Ma,

Li,

Wei

et al. 2024

J Tissue Eng

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Temporomandibular joint (TMJ) cartilage repair poses a considerable clinical challenge, and tissue engineering has emerged as a promising solution. In this study, we developed an injectable reactive oxygen species (ROS)-responsive multifunctional hydrogel (RDGel) to encapsulate dental pulp stem cells (DPSCs/RDGel in short) for the targeted repair of condylar cartilage defect. The DPSCs/RDGel composite exhibited a synergistic effect in the elimination of TMJ OA (osteoarthritis) inflammation via the interaction between the hydrogel component and the DPSCs. We first demonstrated the applicability and biocompatibility of RDGel. RDGel encapsulation could enhance the anti-apoptotic ability of DPSCs by inhibiting P38/P53 mitochondrial apoptotic signal in vitro. We also proved that the utilization of DPSCs/RDGel composite effectively enhanced the expression of TMJOA cartilage matrix and promoted subchondral bone structure in vivo. Subsequently, we observed the synergistic improvement of DPSCs/RDGel composite on the oxidative stress microenvironment of TMJOA and its regulation and promotion of M2 polarization, thereby confirmed that M2 macrophages further promoted the condylar cartilage repair of DPSCs. This is the first time application of DPSCs/RDGel composite for the targeted repair of TMJOA condylar cartilage defects, presenting a novel and promising avenue for cell-based therapy.

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“…To further complicate matters, when ROS alters histone methylation levels alters histone methylation levels, they can give feedback to alter the oxidative stress state, further affecting the development of NAFLD. For example, an aberrant increase in ROS in macrophages induces a decrease in the H3K27me3 demethylase, KDM6A, which leads to an increase in H3K27me3 in the NOX2 promoter, which promotes macrophage M1 polarization and leads to inflammation[ 99 ]. H3K4-specific histone methyltransferase WD repeat sequence-containing protein 5 and histone H3K79 methyltransferase (DOT1L) enhance the activation of the STING-NLRP3-GSDMD axis, promote hepatic ROS generation, and cause hepatocyte apoptosis and liver inflammation in liver fibrosis[ 100 ].…”

Section: Histone Methylation In Fatty Liver Carcinogenesismentioning

confidence: 99%

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Xu,

Fan,

Zhang

et al. 2024

World J Hepatol

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Non-alcoholic fatty liver disease (NAFLD) poses a significant health challenge in modern societies due to shifts in lifestyle and dietary habits. Its complexity stems from genetic predisposition, environmental influences, and metabolic factors. Epigenetic processes govern various cellular functions such as transcription, chromatin structure, and cell division. In NAFLD, these epigenetic tendencies, especially the process of histone methylation, are intricately intertwined with fat accumulation in the liver. Histone methylation is regulated by different enzymes like methyltransferases and demethylases and influences the expression of genes related to adipogenesis. While early-stage NAFLD is reversible, its progression to severe stages becomes almost irreversible. Therefore, early detection and intervention in NAFLD are crucial, and understanding the precise role of histone methylation in the early stages of NAFLD could be vital in halting or potentially reversing the progression of this disease.

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ROS inhibition increases KDM6A-mediated NOX2 transcription and promotes macrophages oxidative stress and M1 polarization

Cited by 4 publications

References 35 publications

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming

Delivery of dental pulp stem cells by an injectable ROS-responsive hydrogel promotes temporomandibular joint cartilage repair via enhancing anti-apoptosis and regulating microenvironment

Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

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