The protein tyrosine kinase SYK regulates the alternative p38 activation in liver during acute liver inflammation

AbstractTwo distinct p38 signaling pathways, classical and alternative, have been identified to regulate inflammatory responses in host defense and disease development. The role of alternative p38 activation in liver inflammation is elusive, while classical p38 signaling in hepatocytes plays a role in regulating the induction of cell death in autoimmune-mediated acute liver injury. In this study, we found that a mutation of alternative p38 in mice augmented the severity of acute liver inflammation. Moreover, TNF-induced hepatocyte death was augmented by a mutation of alternative p38, suggesting that alternative p38 signaling in hepatocytes contributed more significantly to the pathology of acute liver injury. Furthermore, SYK-Vav-1 signaling regulates alternative p38 activation and the downregulation of cell death in hepatocytes. Therefore, it is suggested that alternative p38 signaling in the liver plays a critical role in the induction and subsequent pathological changes of acute liver injury. Collectively, our results imply that p38 signaling in hepatocytes plays a crucial role to prevent excessive liver injury by regulating the induction of cell death and inflammation.

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miR-223 represents a biomarker in acute and chronic liver injury

Clinical Science ◽

10.1042/cs20170218 ◽

2017 ◽

Vol 131 (15) ◽

pp. 1971-1987 ◽

Cited By ~ 18

Author(s):

Florian Schueller ◽

Sanchari Roy ◽

Sven Heiko Loosen ◽

Jan Alder ◽

Christiane Koppe ◽

...

Keyword(s):

Cell Death ◽

Liver Cirrhosis ◽

Liver Fibrosis ◽

Liver Injury ◽

Liver Diseases ◽

Acute Liver Injury ◽

Chronic Liver ◽

Published Data ◽

Duct Ligation

Background: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. Methods: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223−/− mice in these models. Results: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223−/− mice behaved identical with wild-type (wt) mice in all tested models. Conclusion: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.

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Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury

Redox Biology ◽

10.1016/j.redox.2015.09.040 ◽

2015 ◽

Vol 6 ◽

pp. 552-564 ◽

Cited By ~ 26

Author(s):

Sehwan Jang ◽

Li-Rong Yu ◽

Mohamed A. Abdelmegeed ◽

Yuan Gao ◽

Atrayee Banerjee ◽

...

Keyword(s):

Protein Kinase ◽

Liver Injury ◽

Mitochondrial Dysfunction ◽

Acute Liver Injury ◽

Critical Role ◽

Terminal Protein

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Myeloid Differentiation Protein 2 Mediates Angiotensin II-Induced Liver Inflammation and Fibrosis in Mice

Molecules ◽

10.3390/molecules25010025 ◽

2019 ◽

Vol 25 (1) ◽

pp. 25 ◽

Cited By ~ 2

Author(s):

Yi Zhang ◽

Hui Liu ◽

Wenjing Jia ◽

Jiayu Qi ◽

Wentao Zhang ◽

...

Keyword(s):

Angiotensin Ii ◽

Liver Injury ◽

Critical Role ◽

Myeloid Differentiation ◽

Ang Ii ◽

Liver Inflammation ◽

Protein Levels ◽

Extracellular Signal ◽

Injury Model

Angiotensin II (Ang II) participates in the pathogenesis of liver injury. Our previous publications reported that myeloid differentiation protein 2 (MD2) mediates Ang II-induced cardiac and kidney inflammation by directly binding to Ang II. Thus, we hypothesize that MD2 is critical to Ang II-induced liver injury. Subcutaneous injections of Ang II for 8 weeks were adopted to build the liver injury model. With a specific MD2 inhibitor L6H21 and MD2 knockout mice, we reported that MD2 inhibition and knockout significantly mitigate liver inflammation and fibrosis in mice injected with Ang II. To be more specific, the functional and pathological damages induced by Ang II were mitigated by L6H21 or MD2 knockout. MD2 knockout or L6H21 administration inhibited the Ang II-induced upregulation of fibrosis markers, inflammatory cytokines, and adhesion molecules in gene or protein levels. The activation of NF-κB and Extracellular signal-regulated kinases (ERK) induced by Ang II was also reversed by L6H21 treatment or MD2 deficiency. Note that the co-immunoprecipitation study showed that L6H21 downregulated the ANG II-induced toll-like receptor 4 (TLR4)/MD2 complex in liver tissues while having no effects on MD2 expression. Our results reported the critical role of MD2 in the progress of liver injury and suggested that MD2 is a potential therapeutic target for liver injury.

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Critical role of OX40 in drug‐induced acute liver injury

British Journal of Pharmacology ◽

10.1111/bph.15041 ◽

2020 ◽

Vol 177 (14) ◽

pp. 3183-3196

Author(s):

Chunpan Zhang ◽

Hua Jin ◽

Yan Wang ◽

Changying Li ◽

Xinyan Zhao ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Critical Role ◽

Drug Induced

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STING Contributes to Host Defense Against Staphylococcus aureus Pneumonia Through Suppressing Necroptosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.636861 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhen-Zhen Liu ◽

Yong-Jun Yang ◽

Cheng-Kai Zhou ◽

Shi-Qing Yan ◽

Ke Ma ◽

...

Keyword(s):

Cell Death ◽

Host Defense ◽

Early Stage ◽

Critical Role ◽

Adaptor Protein ◽

Tunel Staining ◽

Microbial Infection

STING (Stimulator of interferon genes) is known as an important adaptor protein or direct sensor in the detection of nucleotide originating from pathogens or the host. The implication of STING during pulmonary microbial infection remains unknown to date. Herein, we showed that STING protected against pulmonary S.aureus infection by suppressing necroptosis. STING deficiency resulted in increased mortality, more bacteria burden in BALF and lungs, severe destruction of lung architecture, and elevated inflammatory cells infiltration and inflammatory cytokines secretion. STING deficiency also had a defect in bacterial clearance, but did not exacerbate pulmonary inflammation during the early stage of infection. Interestingly, TUNEL staining and LDH release assays showed that STING-/- mice had increased cell death than WT mice. We further demonstrated that STING-/- mice had decreased number of macrophages accompanied by increased dead macrophages. Our in vivo and in vitro findings further demonstrated this cell death as necroptosis. The critical role of necroptosis was detected by the fact that MLKL-/- mice exhibited decreased macrophage death and enhanced host defense to S.aureus infection. Importantly, blocking necroptosis activation rescued host defense defect against S.aureus pneumonia in STING-/- mice. Hence, these results reveal an important role of STING in suppressing necroptosis activation to facilitate early pathogen control during pulmonary S.aureus infection.

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Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

Seminars in Liver Disease ◽

10.1055/s-0039-1685515 ◽

2019 ◽

Vol 39 (03) ◽

pp. 275-282 ◽

Cited By ~ 5

Author(s):

Alexander Wree ◽

Theresa Maria Holtmann ◽

Maria Eugenia Inzaugarat ◽

Ariel E. Feldstein

Keyword(s):

Cell Death ◽

Liver Injury ◽

Inflammatory Response ◽

Liver Damage ◽

Chronic Liver ◽

Liver Inflammation ◽

Chronic Liver Damage ◽

Recent Developments

AbstractHepatocyte demise as well as signals released by stressed hepatocytes have been now recognized as important triggers of liver inflammation. While traditional concepts classically viewed hepatocyte cell death to occur by either a nonlytic, noninflammatory form (apoptosis), or lytic, proinflammatory nonregulated cell death (necrosis), recent studies have provided evidence for additional mechanisms that can contribute to both acute and chronic liver damage. Two novel forms of cell death, pyroptosis and necroptosis, are of particular importance as they are highly regulated and intrinsically proinflammatory. Additionally, stressed hepatocytes may also release signals to attract and activate monocytes into proinflammatory macrophages. In this review, the authors discuss recent developments supporting the role of novel triggers of liver inflammation in various forms of liver injury and their potential translational implications.

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CD36 deficiency ameliorates drug-induced acute liver injury in mice

Molecular Medicine ◽

10.1186/s10020-021-00325-z ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Chen Zhang ◽

Xiao Shi ◽

Zhongping Su ◽

Chao Hu ◽

Xianmin Mu ◽

...

Keyword(s):

Liver Injury ◽

Western Blot ◽

Kinase Inhibitor ◽

Inflammatory Responses ◽

Acute Liver Injury ◽

Protein Adducts ◽

Sterile Inflammation ◽

Inflammatory Factor ◽

Cd36 Deficiency ◽

Significant Difference

Abstract Background Acetaminophen (APAP) overdose causes hepatotoxicity and even acute liver failure. Recent studies indicate that sterile inflammation and innate immune cells may play important roles in damage-induced hepatocytes regeneration and liver repair. The scavenger receptor CD36 has its crucial functions in sterile inflammation. However, the roles of CD36 in APAP induced acute liver injury remain unclear and warrant further investigation. Methods WT C57BL/6 J and CD36−/− mice were intraperitoneally injected with APAP (300 mg/kg) after fasting for 16 h. Liver injury was evaluated by serum alanine aminotransferase (ALT) level and liver tissue hematoxylin and eosin (H&E) staining. Liver inflammatory factor expression was determined by real-time polymerase chain reaction (PCR). The protein adducts forming from the metabolite of APAP and the metabolism enzyme cytochrome P450 2E1 (CYP2E1) levels were measured by Western blot. Liver infiltrating macrophages and neutrophils were characterized by flow cytometry. RNA sequencing and Western blot were used to evaluate the effect of damage-associated molecular patterns (DAMP) molecule high mobility group B1 (HMGB1) on WT and CD36−/− macrophages. Moreover, PP2, a Src kinase inhibitor, blocking CD36 signaling, was applied in APAP model. Results The expression of CD36 was increased in the liver of mice after APAP treatment. Compared with WT mice, APAP treated CD36−/− mice show less liver injury. There was no significant difference in APAP protein adducts and CYP2E1 expression between these two strains. However, reduced pro-inflammatory factor mRNA expression and serum IL-1β level were observed in APAP treated CD36−/− mice as well as infiltrating macrophages and neutrophils. Moreover, CD36 deficiency impaired the activation of c-Jun N-terminal kinase (JNK) caused by APAP. Interestingly, the lack of CD36 reduced the activation of extracellular regulated protein kinases (Erk) and v-akt murine thymoma viral oncogene homolog (Akt) induced by HMGB1. RNA transcription sequencing data indicated that HMGB1 has a different effect on WT and CD36−/− macrophages. Furthermore, treatment with PP2 attenuated APAP induced mouse liver injury. Conclusion Our data demonstrated that CD36 deficiency ameliorated APAP-induced acute liver injury and inflammatory responses by decreasing JNK activation. CD36 might serve as a new target to reduce acute liver injury.

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The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

International Journal of Molecular Sciences ◽

10.3390/ijms22094370 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4370

Author(s):

Cássia de Fáveri ◽

Paula M. Poeta Fermino ◽

Anna P. Piovezan ◽

Lia K. Volpato

Keyword(s):

Intracellular Signaling ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Critical Role ◽

Integrative Review ◽

Inflammatory Factors ◽

Resolvin D1 ◽

Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

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