Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes

Hakeem, Andrew; Kamal, Mohamed M.; Tawfiq, Rasha A.; Abdelrahman, Basma A.; Hammam, Olfat; Elmazar, Mohamed M.; El-Khatib, Aiman S.; Attia, Yasmeen M.

doi:10.1016/j.biopha.2022.114050

Cited by 6 publications

(7 citation statements)

References 69 publications

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“…Additionally, research conducted by our team has demonstrated that co-culturing peripheral blood mesenchymal stem cells with macrophages can encourage the polarization of macrophages toward M2 type via the IL-10/JAK/STAT3 pathway, as well as reduce the expression and secretion of pro-inflammatory factors while increasing the expression and secretion of anti-inflammatory ones ( 57 ). In studies of enterohepatic crosstalk in nonalcoholic steatohepatitis, it has also been demonstrated that activation of this pathway promotes M2-type macrophage polarization, which ultimately attenuates the intensity of inflammation in intestinal tissues and maintains intestinal homeostasis ( 58 ). Thus, stimulation of the IL-10/JAK/STAT3 signaling pathway may diminish or eliminate inflammation by boosting M2 macrophage polarization, which promotes regenerative tissue repair ( 59 ).…”

Section: Research On the Signaling Pathways Related To Stat3 Regulati...mentioning

confidence: 99%

Advances in the role of STAT3 in macrophage polarization

et al. 2023

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The physiological processes of cell growth, proliferation, differentiation, and apoptosis are closely related to STAT3, and it has been demonstrated that aberrant STAT3 expression has an impact on the onset and progression of a number of inflammatory immunological disorders, fibrotic diseases, and malignancies. In order to produce the necessary biological effects, macrophages (M0) can be polarized into pro-inflammatory (M1) and anti-inflammatory (M2) types in response to various microenvironmental stimuli. STAT3 signaling is involved in macrophage polarization, and the research of the effect of STAT3 on macrophage polarization has gained attention in recent years. In order to provide references for the treatment and investigation of disorders related to macrophage polarization, this review compiles the pertinent signaling pathways associated with STAT3 and macrophage polarization from many fundamental studies.

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Section: Research On the Signaling Pathways Related To Stat3 Regulati...mentioning

confidence: 99%

Advances in the role of STAT3 in macrophage polarization

et al. 2023

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“…Similarly, the PPARδ inhibitor GW0742 reduces LPS-induced TLR4/MyD88 pathway expression, which helps reduce inflammation by blocking the activation of IKKα and NF-κB phosphorylation [ 102 ]. However, the PPAR α/δ dual agonist (Elafibranor, GFT505) restores intestinal integrity in NASH by modulating potential cross-talk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes according to Hakeem [ 103 ]. Furthermore, FXR, a nuclear receptor expressed mainly in the liver and intestine, serves as a bile acid sensor responsible for bile acid homeostasis [ 104 ].…”

Section: Therapeutic Strategies For Mafld Targeting Tlr4 Signaling Pa...mentioning

confidence: 99%

Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways

Ren,

Bai,

et al. 2023

J Innate Immun

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Background: Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases. The underlying pathophysiological mechanisms are intricate and involve various factors. Unfortunately, there is currently a lack of available effective treatment options. Toll-like receptors (TLRs) are a group of pattern-recognition receptors that are responsible for activating the innate immune system. Research has demonstrated that TLR4 plays a pivotal role in the progression of MAFLD by facilitating the pathophysiological mechanisms. Summary: Lipid peroxidation, pro-inflammatory, insulin resistance (IR), and dysbiosis of intestinal microbiota are considered as the pathogenic mechanisms of MAFLD. This review summarizes the impact of TLR4 signaling pathways on the progression of MAFLD, specifically in relation to lipid metabolic disorders, IR, oxidative stress, and gut microbiota disorders. Additionally, we emphasize the potential therapeutic approaches for MAFLD that target TLR4 signaling pathways, including the use of plant extracts, traditional Chinese medicines, probiotics, pharmaceuticals such as PPAR antagonists and FXR agonists, and lifestyle modifications such as dietary changes and exercise also considered. Furthermore, TLR4 signaling pathways have also been linked to the lean MAFLD. Key Messages: TLR4 plays a crucial role in MAFLD by triggering insulin resistance, buildup of lipids, imbalance in gut microbiota, oxidative stress, and initiation of immune responses. The mitigation of MAFLD can be accomplished by suppressing the TLR4 signaling pathway. In the future, it could potentially emerge as a therapeutic target for the condition.

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“…M2 macrophages play a role in tissue repair and wound healing, some cytokines such as IL-6 play dual functions in ALD. IL-10 signaling, by suppressing NF-κB activity and TLR4 responses, plays a pivotal role in this process ( Hakeem et al, 2023 ). IL-6, derived from hepatocytes, has also been identified as a significant stimulus driving the transition from M1 to M2 ( Zhang et al, 2023 ).…”

Section: The Mechanism Of Macrophage Polarization In Alcohol-associat...mentioning

confidence: 99%

“…IL-6, derived from hepatocytes, has also been identified as a significant stimulus driving the transition from M1 to M2 ( Zhang et al, 2023 ). STAT3, a downstream target of IL-10 and IL-6, becomes activated and translocates to the nucleus, where it induces the expression of M2 genes ( Hakeem et al, 2023 ; Zhang et al, 2023 ). Other sources of cytokines like IL-4, IL-13, and transforming growth factor-β (TGF-β) further reinforce M2 polarization through the activation of STAT6 ( Guo et al, 2023 ).…”

Section: The Mechanism Of Macrophage Polarization In Alcohol-associat...mentioning

confidence: 99%

“…Furthermore, elafibranor, a peroxisome proliferator-activated receptors (PPARs)-α/δ dual agonist, has been found to reduce liver steatosis in vitro . It achieves this by promoting M2 polarization, inhibiting M1 polarization, and modulating the TLR4/IFN-γ and IL-10/STAT3 signaling pathways ( Hakeem et al, 2023 ). Recent research has also revealed that miR-34a activates M1 polarization and inhibits M2 polarization through the regulation of Recombinant Sirtuin 1 (Sirt1) ( Wan et al, 2023 ).…”

Section: Therapeutic Implications: Targeting Macrophages In Alcohol-a...mentioning

confidence: 99%

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Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review

Sun,

Zhao,

Shi

et al. 2023

Front. Cell Dev. Biol.

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Alcohol-associated liver disease (ALD) is a condition that develops due to prolonged and excessive alcohol consumption. It encompasses various stages of liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis. Immune cells, particularly macrophages, of various types play a significant role in the onset and progression of the disease. Macrophages observed in the liver exhibit diverse differentiation forms, and perform a range of functions. Beyond M1 and M2 macrophages, human macrophages can polarize into distinct phenotypes in response to various stimuli. Recent advancements have improved our understanding of macrophage diversity and their role in the progression of ALD. This mini-review provides a concise overview of the latest findings on the role and differentiation of macrophages in ALD. Additionally, it discusses potential therapeutic targets associated with macrophages and explores potential therapeutic strategies.

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Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes

Cited by 6 publications

References 69 publications

Advances in the role of STAT3 in macrophage polarization

Advances in the role of STAT3 in macrophage polarization

Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways

Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review

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