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American Journal of Cancer Research 2020Increasing evidence highlights the role of the interleukin (IL)-17 family in pancreatic diseases. IL-17A induces acinar cell injury directly, recruits neutrophils, and... (Review)
Review
Increasing evidence highlights the role of the interleukin (IL)-17 family in pancreatic diseases. IL-17A induces acinar cell injury directly, recruits neutrophils, and cooperates with other inflammatory factors to exacerbate pancreatic inflammation. It also triggers islet β-cell apoptosis and nitric oxide-dependent cytotoxicity, thus aggravating islet inflammation. IL-17A seems to have different roles in pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer (PC). IL-17A participates in the progression of acinar-ductal metaplasia (ADM) and PanIN, but not related to the characteristics of PC stem cells and the overall survival of patients. Acting similar to IL-17A, IL-17B accelerates the invasion and metastasis of PC, and predicts prognosis of PC and the therapeutic effect of gemcitabine. Herein, we review the current understanding of the pathogenesis of IL-17 in pancreatitis, type 1 diabetes mellitus (T1DM), and PC, as well as potential pharmacotherapy targeting IL-17 and its receptors in pancreatic diseases. The findings summarized in this article are of considerable significance for understanding the essential role of IL-17 in pancreatic diseases.
PubMed: 33294254
DOI: No ID Found -
Clinical and Translational Medicine Apr 2023Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the...
BACKGROUND
Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.
METHODS
Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.
RESULTS
We provide evidence that loss of Ca signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.
CONCLUSIONS
These results indicate that loss of Ca signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.
Topics: Humans; Animals; Mice; Sjogren's Syndrome; Alarmins; Salivary Glands; Saliva; Phenotype
PubMed: 37006181
DOI: 10.1002/ctm2.1228 -
Molecular Therapy : the Journal of the... Apr 2022Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on...
Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by cytosolic Ca ([Ca]) overload; however, the underlying mechanisms in Ca overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca entry (SOCE) channel expression, Ca overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of [Ca] in PACs. MiR-26a deficiency increases SOCE channel expression and [Ca] overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with [Ca] overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.
Topics: Acinar Cells; Acute Disease; Animals; Calcium; Calcium Signaling; Humans; Mice; MicroRNAs; Pancreatitis
PubMed: 35077860
DOI: 10.1016/j.ymthe.2022.01.033 -
Cellular and Molecular Gastroenterology... 2022The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant... (Review)
Review
The pancreas consists of several specialized cell types that display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia and intraductal papillary neoplasms, precursor lesions to pancreatic ductal adenocarcinoma. In the face of shifting cellular identity, the cell of origin of pancreatic cancer has been difficult to elucidate. However, with the extensive utilization of in vivo lineage-traced mouse models coupled with insights from human samples, it has emerged that the acinar cell is most efficiently able to give rise to both intraductal papillary neoplasms and pancreatic intraepithelial neoplasia but that acinar and ductal cells can undergo malignant transformation to pancreatic ductal adenocarcinoma. In this review, we discuss the cellular reprogramming that takes place in both the normal and malignant pancreas and evaluate the current state of evidence that implicate both the acinar and ductal cell as context-dependent origins of this deadly disease.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cell Plasticity; Mice; Pancreas; Pancreatic Neoplasms
PubMed: 34352406
DOI: 10.1016/j.jcmgh.2021.07.014 -
Frontiers in Immunology 2022Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and...
Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and necroptosis are involved in this process, but the relationships between them remain unknown. Here, we analyzed the interaction between ER stress and necroptosis and the underlying mechanisms during AP. Experimental pancreatitis was induced in Balb/C mice by caerulein (Cae) and lipopolysaccharide (LPS) or L-arginine (L-Arg) , and pancreatic acinar cells were also used to follow cellular mechanisms during cholecystokinin (CCK) stimulation . AP severity was assessed by serum amylase, lipase levels and histological examination. Changes in ER stress, trypsinogen activation and necroptosis levels were analyzed by western blotting, enzyme-linked immunosorbent assay (ELISA), adenosine triphosphate (ATP) analysis or lactate dehydrogenase (LDH) assay. The protein kinase C (PKC)α -mitogen-activated protein kinase (MAPK) -cJun pathway and cathepsin B (CTSB) activation were evaluated by western blotting. Activating protein 1 (AP-1) binding activity was detected by electrophoretic mobility shift assay (EMSA). We found that ER stress is initiated before necroptosis in CCK-stimulated acinar cells . Inhibition of ER stress by 4-phenylbutyrate (4-PBA) can significantly alleviate AP severity both in two AP models . 4-PBA markedly inhibited ER stress and necroptosis of pancreatic acinar cells both and . Mechanistically, we found that 4-PBA significantly reduced CTSB maturation and PKCα-JNK-cJun pathway -mediated AP-1 activation during AP. Besides, CTSB inhibitor CA074Me markedly blocked PKCα-JNK-cJun pathway -mediated AP-1 activation and necroptosis in AP. However, pharmacologic inhibition of trypsin activity with benzamidine hydrochloride had no effect on PKCα-JNK-cJun pathway and necroptosis in CCK-stimulated pancreatic acinar cells. Furthermore, SR11302, the inhibitor of AP-1, significantly lowered tumor necrosis factor (TNF) α levels, and its subsequent receptor interacting protein kinases (RIP)3 and phosphorylated mixed lineagekinase domain-like (pMLKL) levels, ATP depletion and LDH release rate in CCK-stimulated pancreatic acinar cells. To sum up, all the results indicated that during AP, ER stress promoted pancreatic acinar cell necroptosis through CTSB maturation, thus induced AP-1 activation and TNFα secretion PKCα-JNK-cJun pathway, not related with trypsin activity. These findings provided potential therapeutic target and treatment strategies for AP or other cell death-related diseases.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Animals; Cathepsin B; Endoplasmic Reticulum Stress; Mice; Mice, Inbred BALB C; Necroptosis; Pancreatitis; Protein Kinase C-alpha; Transcription Factor AP-1; Trypsin
PubMed: 36059491
DOI: 10.3389/fimmu.2022.968639 -
PloS One 2023Proper maintenance of mature cellular phenotypes is essential for stable physiology, suppression of disease states, and resistance to oncogenic transformation. We...
Proper maintenance of mature cellular phenotypes is essential for stable physiology, suppression of disease states, and resistance to oncogenic transformation. We describe the transcriptional regulatory roles of four key DNA-binding transcription factors (Ptf1a, Nr5a2, Foxa2 and Gata4) that sit at the top of a regulatory hierarchy controlling all aspects of a highly differentiated cell-type-the mature pancreatic acinar cell (PAC). Selective inactivation of Ptf1a, Nr5a2, Foxa2 and Gata4 individually in mouse adult PACs rapidly altered the transcriptome and differentiation status of PACs. The changes most emphatically included transcription of the genes for the secretory digestive enzymes (which conscript more than 90% of acinar cell protein synthesis), a potent anabolic metabolism that provides the energy and materials for protein synthesis, suppressed and properly balanced cellular replication, and susceptibility to transformation by oncogenic KrasG12D. The simultaneous inactivation of Foxa2 and Gata4 caused a greater-than-additive disruption of gene expression and uncovered their collaboration to maintain Ptf1a expression and control PAC replication. A measure of PAC dedifferentiation ranked the effects of the conditional knockouts as Foxa2+Gata4 > Ptf1a > Nr5a2 > Foxa2 > Gata4. Whereas the loss of Ptf1a or Nr5a2 greatly accelerated Kras-mediated transformation of mature acinar cells in vivo, the absence of Foxa2, Gata4, or Foxa2+Gata4 together blocked transformation completely, despite extensive dedifferentiation. A lack of correlation between PAC dedifferentiation and sensitivity to oncogenic KrasG12D negates the simple proposition that the level of differentiation determines acinar cell resistance to transformation.
Topics: Mice; Animals; Acinar Cells; Pancreas, Exocrine; Epithelium; Transcription Factors; Cell Transformation, Neoplastic; Phenotype; Pancreatic Neoplasms
PubMed: 37796967
DOI: 10.1371/journal.pone.0291512 -
Cell Death & Disease Oct 2022Acinar-to-ductal metaplasia (ADM) is a precursor lesion of pancreatic ductal adenocarcinoma (PDAC); however, the regulators of the ADM-mediated PDAC development and its...
Acinar-to-ductal metaplasia (ADM) is a precursor lesion of pancreatic ductal adenocarcinoma (PDAC); however, the regulators of the ADM-mediated PDAC development and its targeting are poorly understood. RNA polymerase II-associated factor 1 (PAF1) maintains cancer stem cells leading to the aggressiveness of PDAC. In this study, we investigated whether PAF1 is required for the YAP1-mediated PDAC development and whether CA3 and verteporfin, small molecule inhibitors of YAP1/TEAD transcriptional activity, diminish pancreatic cancer (PC) cell growth by targeting the PAF1/YAP1 axis. Here, we demonstrated that PAF1 co-expresses and interacts with YAP1 specifically in metaplastic ducts of mouse cerulein- or Kras-induced ADM and human PDAC but not in the normal pancreas. PAF1 knockdown (KD) reduced SOX9 in PC cells, and the PC cells showed elevated PAF1/YAP1 complex recruitment to the promoter of SOX9. The PAF1 KD reduced the 8xTEAD and SOX9 promoter-luciferase reporter activities in the mouse KC (Kras; Pdx-1 Cre) cells and human PC cells, indicating that the PAF1 is required for the YAP1-mediated development of ADM and PC. Moreover, treatment with CA3 or verteporfin reduced the expressions of PAF1, YAP1, TEAD4, and SOX9 and decreased colony formation and stemness in KC and PC cells. CA3 treatment also reduced the viability and proliferation of PC cells and diminished the duct-like structures in KC acinar explants. CA3 or verteporfin treatment decreased the recruitment of the PAF1/YAP1 complex to the SOX9 promoter in PC cells and reduced the 8xTEAD and SOX9 promoter-luciferase reporter activities in KC and PC cells. Overall, PAF1 cooperates with YAP1 during ADM and PC development, and verteporfin and CA3 inhibit ADM and PC cell growth by targeting the PAF1/YAP1/SOX9 axis in vitro and ex vivo models. This study identified a regulatory axis of PDAC initiation and its targeting, paving the way for developing targeted therapeutic strategies for pancreatic cancer patients.
Topics: Acinar Cells; Animals; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Ceruletide; DNA-Binding Proteins; Humans; Luciferases; Metaplasia; Mice; Pancreatic Ducts; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); RNA Polymerase II; TEA Domain Transcription Factors; Transcription Factors; Verteporfin; YAP-Signaling Proteins
PubMed: 36180487
DOI: 10.1038/s41419-022-05258-x -
International Journal of Medical... 2023Acinar epithelial cell atrophy in secretory glands is a hallmark of primary Sjögren's syndrome (pSS), the cause of which is far from elucidated. We examined the role of...
Acinar epithelial cell atrophy in secretory glands is a hallmark of primary Sjögren's syndrome (pSS), the cause of which is far from elucidated. We examined the role of acinar atrophy by focusing on the metabolism of glandular epithelial cells and mitochondria in the pSS environment. After confirming the presence of a high-lactate environment in the labial glands of human pSS patients, we used the A253 cell line and NOD/Ltj mice as models to investigate the metabolic changes in salivary gland epithelial cells in a high-lactate environment and . We found that epithelial cells produced high levels of IL-6, IL-8, IFN-α, IFN-β and TNF-α and exhibited significant NF-κB and type I IFN-related pathway activation. The results confirmed that lactate damaged mitochondrial DNA (mtDNA) and led to its leakage, which subsequently activated the cGAS-STING pathway. Inflammatory cytokine production and pathway activation were inhibited and by the lactate scavenger sodium dichloroacetate (DCA). Our study provides new insights into the etiology and treatment of pSS from the perspective of cell metabolism.
Topics: Mice; Animals; Humans; Sjogren's Syndrome; Salivary Glands; DNA, Mitochondrial; Lactic Acid; Mice, Inbred NOD; Nucleotidyltransferases; Mitochondria
PubMed: 37786436
DOI: 10.7150/ijms.83801 -
Science Advances Dec 2022Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With...
Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here, using the adult murine system, we demonstrate that radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week after radiation, with extensive acinar cell degeneration, dysfunction, and cholinergic denervation occurring thereafter. However, we found that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline-alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at nonirradiated levels over the long term (>3 months). Thus, we reveal a previously unknown regenerative approach for restoring epithelial organ structure and function that has extensive implications for human patients.
PubMed: 36542703
DOI: 10.1126/sciadv.adc8753 -
Gastroenterology May 2024Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM...
BACKGROUND & AIMS
Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human.
METHODS
We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26; Sox4) with and without an activating mutation in Kras (Kras). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing.
RESULTS
We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression.
CONCLUSIONS
Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.
PubMed: 38729450
DOI: 10.1053/j.gastro.2024.04.031