Multicombination Approach Suppresses <i>Listeria monocytogenes</i>‐Induced Septicemia‐Associated Acute Hepatic Failure: The Role of iRhom2 Signaling

Xu, Minxuan; Ge, Chenxu; Qin, Yuting; Gu, Ting-Ting; Lou, Deshuai; Li, Qiang; Hu, Lin‐Feng; Tan, Jun

doi:10.1002/adhm.201800427

Cited by 18 publications

(11 citation statements)

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“…Inactive rhomboid protein 2 (iRhom2), also known as Rhbdf2, is an inactive member of the rhomboid intramembrane proteinase family of serine proteases that has been shown to be involved in the regulation and trafficking of inflammatory responses. (12)(13)(14)(15) With the alteration of the innate immunity status, iRhom2 activity in macrophages is markedly up-regulated, and iRhom2 enhances maturation and secretion of TNFα through trafficking with a disintegrin and metalloprotease 17 (ADAM17), activating downstream signaling cascades involving TNFα, phosphorylated NF-κB, and various cytokines or chemokines, thereby strengthening the inflammatory reaction and promoting macrophage infiltration. (15) These recent studies have reported various ways in which iRhom2 regulates stimulus-mediated immune responses in viral infection, inflammatory injury, and hepatic failure.…”

Section: Irhom2 Promotes Hepatic Steatosis By Activating Map3k7-depen...mentioning

confidence: 99%

“…( 16 ) Furthermore, iRhom2 overactivation facilitates inflammatory responses in acute hepatic injury and systemic metabolism syndrome. ( 15 ) However, to the best of our knowledge, a role of iRhom2 in systemic insulin resistance, inflammation, or hepatic steatosis has not been reported. In light of these findings, there is an urgent need to explain the exact role of iRhom2 in the development and progression of hepatic inflammation, steatosis, and insulin resistance.…”

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confidence: 92%

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iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7‐Dependent Pathway

Zhu

et al. 2021

Hepatology

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Background and Aims Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD‐associated metabolic disorder. Inactive rhomboid‐like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2‐regulated inflammation promotes NAFLD progression remain to be elucidated. Approach and Results Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2‐deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high‐fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen‐activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c‐Jun N‐terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β–associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2‐regulated liver steatosis. Conclusions iRhom2 may represent a therapeutic target for the treatment of HFD‐induced hepatic steatosis and insulin resistance.

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Section: Irhom2 Promotes Hepatic Steatosis By Activating Map3k7-depen...mentioning

confidence: 99%

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confidence: 92%

iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7‐Dependent Pathway

Zhu

et al. 2021

Hepatology

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“…As we previously reported, iRhom2 was involved in hepatic injury induced by PM 2.5 through modulating inflammatory response, and loss of iRhom2 significantly attenuated PM 2.5 -triggered inflammation in liver tissue samples, along with remarkable reduction of TACE/TNFRs [17] . Recently, we reported that reducing iRhom2 could alleviate acute hepatic injury by blocking inflammatory response [24] . Therefore, we hypothesized that iRhom2 might be also involved in the regulation of renal function.…”

Section: Introductionmentioning

confidence: 99%

iRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress

Qin

et al. 2018

Redox Biology

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Particulate matter (PM2.5) is a risk factor for organ injury and disease progression, such as lung, brain and liver. However, its effects on renal injury and the underlying molecular mechanism have not been understood. The inactive rhomboid protein 2 (iRhom2), also known as rhomboid family member 2 (Rhbdf2), is a necessary modulator for shedding of tumor necrosis factor-α (TNF-α) in immune cells, and has been explored in the pathogenesis of chronic renal diseases. In the present study, we found that compared to the wild type (iRhom2+/+) mice, iRhom2 knockout (iRhom2-/-) protected PM2.5-exposed mice from developing severe renal injury, accompanied with improved renal pathological changes and functions. iRhom2-/- mice exhibited reduced inflammatory response, as evidenced by the reduction of interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) and IL-18 in kidney samples, which might be, at least partly, through inactivating TNF-α converting enzyme/TNF-α receptors (TACE/TNFRs) and inhibitor of α/nuclear factor κ B (IκBα/NF-κB) signaling pathways. In addition, oxidative stress was also restrained by iRhom2-/- in kidney of PM2.5-exposed mice by enhancing heme oxygenase/nuclear factor erythroid 2-related factor 2 (HO-1/Nrf-2) expressions, and reducing phosphorylated c-Jun N-terminal kinase (JNK). In vitro, blockage of HO-1 or Nrf-2 rescued the inflammatory response and oxidative stress that were reduced by iRhom2 knockdown in PM2.5-incubated RAW264.7 cells. Similar results were observed in JNK activator-treated cells. Taken together, our findings indicated that iRhom2 played an essential role in regulating PM2.5-induced chronic renal damage, thus revealing a potential target for preventing chronic kidney diseases development.

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“…Fisetin, a natural antioxidant, is found in various vegetables and fruits [ 138 , 139 ]. TNF-α inhibitor manifested excellent anti-inflammatory and antioxidant effects in Listeria monocytogenes induced fatal septicemia-associated ALF [ 140 ]. The nanocomposite inhibited macrophage activation-related inactive rhomboid protein 2/TNF-α converting enzyme/TNF-α signaling and restored nuclear factor erythroid-2-related factor 2 to relieve Listeria monocytogenes-induced metabolic disorder and septicemia-associated systemic inflammation.…”

Section: Nanomedicine For Therapy Of Acute Liver Failurementioning

confidence: 99%

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

Jin

Wang

et al. 2020

Nano-Micro Lett.

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Highlights This review focuses on the therapeutic mechanisms, targeting strategies of various nanomaterials in acute liver failure, and recent advances of diverse nanomaterials for acute liver failure therapy, diagnosis, and imaging. This review provides an outlook on the applications of nanomaterials, especially on the new horizons in acute liver failure therapy, and inspires broader interests across various disciplines. Abstract Acute liver failure (ALF), a fatal clinical disease featured with overwhelming hepatocyte necrosis, is a grand challenge in global health. However, a satisfactory therapeutic option for curing ALF is still absent, other than liver transplantation. Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF. The liver can sequester most of nanoparticles from blood circulation, which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases. Nanobiomaterials can enhance the bioavailability of free drugs, thereby significantly improving the therapeutic effects in ALF. Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells. In addition, stimuli-responsive, optical, or magnetic nanomaterials exhibit great potential in the therapeutical, diagnostic, and imaging applications in ALF. Therefore, therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy, diminish adverse systemic effects, and offer a multifunctional theranostic platform. Nanobiomaterial holds excellent significance and prospects in ALF theranostics. In this review, we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF. We highlight recent developments of diverse nanomedicines for ALF therapy, diagnosis, and imaging. Furthermore, the challenges and future perspectives in the theranostics of ALF are also discussed.

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Multicombination Approach Suppresses Listeria monocytogenes‐Induced Septicemia‐Associated Acute Hepatic Failure: The Role of iRhom2 Signaling

Cited by 18 publications

References 73 publications

iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7‐Dependent Pathway

iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7‐Dependent Pathway

iRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

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