Endoplasmic reticulum stress promoted acinar cell necroptosis in acute pancreatitis through cathepsinB-mediated AP-1 activation

Han, Xiao; Li, Bin; Bao, Jingpiao; Wu, Zengkai; Chen, Congying; Ni, Jiahua; Shen, Jie; Song, Pengli; Peng, Qi; Wan, Rong; Wang, Xingpeng; Wu, Jianghong; Hu, Guoyong

doi:10.3389/fimmu.2022.968639

Cited by 15 publications

(5 citation statements)

References 46 publications

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“…Moreover, pretreatment with SR11302 prior to the addition of ALN inhibited ALN-augmented LDH release by RAW264 cells, suggesting that ALN might augment cell membrane damage via AP-1 activation. This result is consistent with previous reports showing that activation of AP-1 induced the pyroptosis of hepatocytes, apoptosis of cardiomyocytes and necroptosis of acinar cells (35)(36)(37). SR11302 is a synthetic retinoid that inhibits AP-1 activity without activating transcription through the retinoic acid response element, although retinoic acid has also been reported to attenuate expression of the NLRP3 inflammasome in macrophages (38,39).…”

Section: Discussionsupporting

confidence: 93%

Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation

Watanabe,

Tamai,

Kiyoura

2023

Exp Ther Med

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Alendronate (ALN) is an anti-bone-resorptive drug with inflammatory side effects. ALN upregulates lipid A-induced interleukin (IL)-1α and IL-1β release by J774.1 cells via apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) activation. The present study examined whether ALN augmented lipid A-induced proinflammatory cytokine production using ASC-deficient mouse macrophage-like RAW264 cells. Pretreatment of RAW264 cells with ALN significantly augmented lipid A-induced IL-1β release, although ALN did not upregulate the expression of Toll-like receptor 4, myeloid differentiation factor 88 (MyD88) and caspase-11. Moreover, pretreatment of caspase-11-deficient RAW264.7 cells with ALN significantly augmented lipid A-induced IL-1β release. Notably, ALN upregulated the activation of FosB, c-Jun or JunD, but not c-Fos or NF-κB in RAW264 cells. Furthermore, pretreatment with the activator protein 1 (AP-1) inhibitor SR11302, but not the c-Fos inhibitor T-5224, before addition of ALN inhibited ALN-augmented IL-1β release by lipid A-treated RAW264 cells. SR11302 also reduced ALN-augmented lactate dehydrogenase release by the cells. These findings collectively suggested that ALN augmented lipid A-induced IL-1β release and cell membrane damage in ASC-deficient RAW264 cells via activation of AP-1, but not NF-κB.

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Section: Discussionsupporting

confidence: 93%

Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation

Watanabe,

Tamai,

Kiyoura

2023

Exp Ther Med

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“…PKCα is an upstream regulator of JNK and promotes its recruitment to cellular membranes ( 94 – 102 ). Cdc42 is also as an upstream activator of JNK ( 11 , 103 – 106 ).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the induction of JNK phosphorylation by C1P was abolished by Cdc42 downregulation suggesting that Cdc42 is downstream of PKCα and upstream of JNK. As PKCα also activates JNK ( 94 – 102 ), we investigated if C1P induces JNK phosphorylation by PKCα-dependent signaling. Gö6976 pronouncedly repressed C1P-mediated JNK phosphorylation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Ceramide-1-phosphate is a regulator of Golgi structure and is co-opted by the obligate intracellular bacterial pathogen Anaplasma phagocytophilum

Read,

Ali,

Stephenson

et al. 2024

mBio

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Many intracellular pathogens structurally disrupt the Golgi apparatus as an evolutionarily conserved promicrobial strategy. Yet, the host factors and signaling processes involved are often poorly understood, particularly for Anaplasma phagocytophilum , the agent of human granulocytic anaplasmosis. We found that A. phagocytophilum elevated cellular levels of the bioactive sphingolipid, ceramide-1-phosphate (C1P), to promote Golgi fragmentation that enables bacterial proliferation, conversion from its non-infectious to infectious form, and productive infection. A. phagocytophilum poorly infected mice deficient in ceramide kinase, the Golgi-localized enzyme responsible for C1P biosynthesis. C1P regulated Golgi morphology via activation of a PKCα/Cdc42/JNK signaling axis that culminates in phosphorylation of Golgi structural proteins, GRASP55 and GRASP65. siRNA-mediated depletion of Cdc42 blocked A. phagocytophilum from altering Golgi morphology, which impaired anterograde trafficking of trans -Golgi vesicles into and maturation of the pathogen-occupied vacuole. Cells overexpressing phosphorylation-resistant versions of GRASP55 and GRASP65 presented with suppressed C1P- and A. phagocytophilum -induced Golgi fragmentation and poorly supported infection by the bacterium. By studying A. phagocytophilum , we identify C1P as a regulator of Golgi structure and a host factor that is relevant to disease progression associated with Golgi fragmentation. IMPORTANCE Ceramide-1-phosphate (C1P), a bioactive sphingolipid that regulates diverse processes vital to mammalian physiology, is linked to disease states such as cancer, inflammation, and wound healing. By studying the obligate intracellular bacterium Anaplasma phagocytophilum , we discovered that C1P is a major regulator of Golgi morphology. A. phagocytophilum elevated C1P levels to induce signaling events that promote Golgi fragmentation and increase vesicular traffic into the pathogen-occupied vacuole that the bacterium parasitizes. As several intracellular microbial pathogens destabilize the Golgi to drive their infection cycles and changes in Golgi morphology is also linked to cancer and neurodegenerative disorder progression, this study identifies C1P as a potential broad-spectrum therapeutic target for infectious and non-infectious diseases.

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“…Our study confirms the induction of ferroptosis in AP and HTGP models. Recent research indicates that ERS plays a crucial role in promoting pancreatitis 26 , contributing to lipid deregulation 27 . In the present study, the activity of a series of proteins, including Bip, CHOP, EIF2α, and p-EIF2α were assessed in rat pancreas (Fig.…”

Section: Ers Participation In Ferroptosis Induced By Htg and Cerulein...mentioning

confidence: 99%

Liproxstatin-1 attenuates acute hypertriglyceridemic pancreatitis through inhibiting ferroptosis in rats

Xiang,

Xu,

Liu

et al. 2024

Sci Rep

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Ferroptosis is closely associated with inflammatory diseases, including acute pancreatitis (AP); however, the involvement of ferroptosis in hypertriglyceridemic pancreatitis (HTGP) remains unclear. In the present study, we aimed to explore the relationship between lipid metabolism and ferroptosis in HTGP and the alleviating effect of liproxstatin-1 (Lip-1) in vivo. This study represents the first exploration of lipid metabolism and endoplasmic reticulum stress (ERS) in HTGP, targeting ferroptosis as a key factor in HTGP. Hypertriglyceridemia (HTG) was induced under high-fat diet conditions. Cerulein was then injected to establish AP and HTGP models. Lip-1, a specific ferroptosis inhibitor, was administered before the induction of AP and HTGP in rats, respectively. Serum triglyceride, amylase, inflammatory factors, pathological and ultrastructural structures, lipid peroxidation, and iron overload indicators related to ferroptosis were tested. Moreover, the interaction between ferroptosis and ERS was assessed. We found HTG can exacerbate the development of AP, with an increased inflammatory response and intensified ferroptosis process. Lip-1 treatment can attenuate pancreatic injury by inhibiting ferroptosis through lipid metabolism and further resisting activations of ERS-related proteins. Totally, our results proved lipid metabolism can promote ferroptosis in HTGP by regulating ACSL4/LPCAT3 protein levels. Additionally, ERS may participate in ferroptosis via the Bip/p-EIF2α/CHOP pathway, followed by the alleviating effect of Lip-1 in the rat model.

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Endoplasmic reticulum stress promoted acinar cell necroptosis in acute pancreatitis through cathepsinB-mediated AP-1 activation

Cited by 15 publications

References 46 publications

Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation

Alendronate augments lipid A‑induced IL‑1β release by ASC‑deficient RAW264 cells via AP‑1 activation

Ceramide-1-phosphate is a regulator of Golgi structure and is co-opted by the obligate intracellular bacterial pathogen Anaplasma phagocytophilum

Liproxstatin-1 attenuates acute hypertriglyceridemic pancreatitis through inhibiting ferroptosis in rats

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