Macrophage‐derived MLKL in alcohol‐associated liver disease: Regulation of phagocytosis

Wu, Xiaoqin; Fan, Xiude; McMullen, Megan R.; Miyata, Tatsunori; Kim, Adam; Pathak, Vai; Wu, Jiang; Day, Le; Hardesty, Josiah; Dasarathy, Srinivasan; Dasarathy, Jaividhya; Allende, Daniela S.; McCullough, Arthur J.; Jacobs, Jon; Rotroff, Daniel M.; Dasarathy, Srinivasan; Nagy, Laura E.

doi:10.1002/hep.32612

Cited by 24 publications

(21 citation statements)

References 44 publications

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“…Moreover, the specific functions of MLKL in different cell types could also influence liver inflammation and pathology. A recent study highlighted that the absence of Mlkl specifically in myeloid cells exacerbated ethanol-induced hepatic injury, steatosis, and inflammation in mice (49). Therefore, further research is needed to explore the impact of cell type-specific effects of MLKL on MASH, underscoring the intricate nature of MLKL’s involvement in liver pathology and expanding its potential functions beyond conventional associations with necroptosis.…”

Section: Discussionmentioning

confidence: 99%

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

Ohene-Marfo,

Nguyen,

Mohammed

et al. 2024

Preprint

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Chronic inflammation is a key player in metabolic dysfunction-associated fatty liver disease (MAFLD) progression. Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD mouse model. Despite HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl-/- mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+/- mice showed significant reduction in these parameters that was associated with elevated Pparα and Pparγ levels. Both Mlkl-/- and Mlkl+/- mice on HFHFrHC diet resisted diet-induced obesity, attributed to increased beiging, enhanced oxygen consumption and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue specific effects of MLKL on the liver and adipose tissue, and suggest a dose-dependent effect of MLKL on liver pathology.

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Section: Discussionmentioning

confidence: 99%

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

Ohene-Marfo,

Nguyen,

Mohammed

et al. 2024

Preprint

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show abstract

“…Emerging evidences have suggested the role of MLKL in regulating immune cells including macrophages. Increased MLKL expression in macrophages was found in ethanol-exposed livers, and myeloid MLKL deficiency exacerbated ethanol-induced steatosis and hepatocyte injury by impairing macrophage phagocytic capability [18]. Inhibition of RIPK1 improves NASH in an MLKL-dependent manner to increase mitochondrial respiration [47].…”

Section: Discussionmentioning

confidence: 99%

“…Another study also showed that alcoholic steatosis-promoted IR injury is independent of MLKL-mediated necroptosis [17]. Moreover, MLKL has been reported to regulate macrophage phagocytosis [18] and hepatocyte autophagy [19] in a necroptosis-independent manner. Therefore, the precise role and underlying mechanism of MLKL in regulating liver IR injury needs to be further studied.…”

Section: Introductionmentioning

confidence: 91%

MLKL deficiency attenuated hepatocyte oxidative DNA damage by activating mitophagy to suppress macrophage cGAS-STING signaling during liver ischemia and reperfusion injury

Zhou

et al. 2023

Cell Death Discov.

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Mixed-lineage kinase domain-like protein (MLKL)-mediated necroptosis has been implicated in aggravating liver ischemia and reperfusion (IR) injury. However, the precise role and mechanism of MLKL in regulating oxidative DNA damage of hepatocytes and subsequent activation of macrophage stimulator of interferon genes (STING) signaling remains unclear. In this study, we investigated the role of MLKL in regulating the interplay between hepatocyte injury and macrophage pro-inflammatory responses during liver IR injury. We found that IR increased MLKL expression in liver tissues of wild type (WT) mice. MLKL knockout (KO) attenuated liver IR injury and suppressed the activation of cGAS-STING signaling in intrahepatic macrophages, which was abrogated by STING activation with its agonist. Mechanistically, IR induced oxidative DNA damage in hepatocytes, leading to cGAS-STING activation in macrophages, which was suppressed by MLKL KO. Moreover, increased PTEN-induced kinase 1 (PINK1)-mediated mitophagy contributed to reduced oxidative DNA damage in hepatocytes and subsequent decreased activation of STING signaling in macrophages in MLKL KO mice. Our findings demonstrated a non-canonical role of MLKL in the pathogenesis of liver IR. MLKL deficiency significantly promoted PINK1-mediated mitophagy activation to inhibit oxidative DNA damage in hepatocytes, which in turn suppressed macrophage cGAS-STING activation and inflammatory liver IR injury.

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“…It has been reported that LPS can regulate MLKL expression. Wu et al 21 found that challenging macrophages with LPS-induced phosphorylation of MLKL, as well as translocation and oligomerization of MLKL to intracellular compartments including phagosomes and lysosomes, but not plasma membrane. Knockdown MLKL suppressed the phagocytic capability of primary mouse Kupffer cells at baseline and in response to LPS.…”

Section: Discussionmentioning

confidence: 99%

Some Macrophages With High Expression of CHOP Undergo Necroptosis in Chronic Rhinosinusitis

et al. 2023

Am J Rhinol�Allergy

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Background Endoplasmic reticulum stress (ER stress) is activated in chronic sinusitis with nasal polyps (CRSwNP) and leads to increased expression of C/EBP homologous protein (CHOP). However, the role of CHOP in the pathogenesis of CRSwNP remains unclear. Methods CHOP expression was detected by immunohistochemistry staining in nasal mucosa of control and CRSwNP patients. Co-localization of CHOP and cleaved caspase3, p-MLKL, and CD68 was detected by immunofluorescence staining in CRSwNP patients. TNFα, IFNγ, IL1β, LPS, and tunicamycin were added to primary dispersed nasal polyp cells (DNPCs) to explore their roles in cell death. Western blot, CCK8 assay, and flow cytometry were employed to detect cell death. Results CHOP was specifically activated in CRSwNP compared to controls. It was mainly macrophages that highly expressed CHOP, some of which underwent apoptosis and the other underwent necroptosis. IL1β induced increased CHOP and apoptosis, and a slight p-MLKL. In addition, ER stress could also promote p-MLKL expression. Whereas classical TNFα plus IFNγ and LPS did not induce increased necroptosis in DNPCs. Conclusion IL1β induced the apoptotic pathway and minor necroptosis. And ER stress also plays a role in the occurrence of necroptosis in CRSwNP.

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Macrophage‐derived MLKL in alcohol‐associated liver disease: Regulation of phagocytosis

Cited by 24 publications

References 44 publications

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High Fat, High Fructose, High Cholesterol Diet Mouse Model

MLKL deficiency attenuated hepatocyte oxidative DNA damage by activating mitophagy to suppress macrophage cGAS-STING signaling during liver ischemia and reperfusion injury

Some Macrophages With High Expression of CHOP Undergo Necroptosis in Chronic Rhinosinusitis

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