Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice

Sendler, Matthias; Weiss, Frank Ulrich; Golchert, Janine; Homuth, Georg; Brandt, Cindy van den; Mahajan, Ujjwal Mukund; Partecke, Lars-Ivo; Döring, Paula; Gukovsky, Ilya; Gukovskaya, Anna S.; Wagh, Preshit Ravindra; Lerch, Markus M.; Mayerle, Julia

doi:10.1053/j.gastro.2017.10.018

Cited by 194 publications

(234 citation statements)

References 58 publications

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“…Injured acinar cells initiate inflammatory responses by releasing proinflammatory cytokines, digestive enzymes, and nuclear damage-associated molecular patterns molecules, which attract and activate immune cell to exacerbate tissue injury 20, 21 . It has been demonstrated that pancreatic acinar cells undergo necrosis when exposed to supraphysiological cerulein in vitro 22 .…”

Section: Resultsmentioning

confidence: 99%

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Huang

Wang

et al. 2019

Preprint

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2Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the 3 pancreas but the transcriptional program underlying these changes is incompletely understood. 4The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and 5 its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and 6 migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar 7 cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human 8 pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated 9 carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and 10 pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a CreER ;Prdm3 flox/flox mice) in the 11 context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In 12Prdm3-deficient mice, Kras G12D -driven preneoplastic lesions were more abundant and progressed 13 to high-grade precancerous lesions more rapidly. This is consistent with our observations that 14 low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. 15Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell 16 activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon 17 cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed 18 that pathways involved in inflammatory response and Hif-1 signaling were significantly 19 upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 20 favors the maintenance of acinar cell homeostasis through modulation of their response to 21 inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive 22 role during PDAC initiation. 23

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Section: Resultsmentioning

confidence: 99%

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Huang

Wang

et al. 2019

Preprint

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“…To mimic pancreatitis caused by pancreatic duct obstruction (e.g., gallstones), we used a mouse model of pancreatitis by ligating the tail region of the pancreas for 24 hours (83). In this model, we observed that TRPV4-KO mice were substantially protected.…”

Section: Discussionmentioning

confidence: 99%

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation

Swain

Romac

Shahid

et al. 2020

Journal of Clinical Investigation

129

127

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“…Activated pro-inflammatory macrophages (M1) release copious amounts of cytokines, including interleukin 6 (IL6), IL12, IL1β and tumour necrosis factor alpha (TNFα), early in the inflammatory response and in AP make a significant contribution to the systemic inflammatory response syndrome linked to organ dysfunction and death [12]. Recently extra-acinar protease activation within macrophages during endocytosis of zymogen-containing vesicles has been shown to participate in the systemic inflammatory response and determine AP severity [39]. In our study, the PMA-induced ECAR response of AP patient monocytes was also greater than those of healthy volunteers, indicating an enhanced glycolytic component of ATP production during the respiratory burst with prioritisation of cellular oxygen to generate free radicals.…”

Section: Discussionmentioning

confidence: 99%

Altered Bioenergetics of Blood Cell Sub-Populations in Acute Pancreatitis Patients

Morton

Armstrong

Sud

et al. 2019

JCM

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Acute pancreatitis (AP) is a debilitating, sometimes fatal disease, marked by local injury and systemic inflammation. Mitochondrial dysfunction is a central feature of pancreatic damage in AP, however, its involvement in circulating blood cell subtypes is unknown. This study compared mitochondrial bioenergetics in circulating leukocytes from AP patients and healthy volunteers: 15 patients with mild to severe AP were compared to 10 healthy controls. Monocytes, lymphocytes and neutrophils were isolated using magnetic activated cell sorting and mitochondrial bioenergetics profiles of the cell populations determined using a Seahorse XF24 flux analyser. Rates of oxygen consumption (OCR) and extracellular acidification (ECAR) under conditions of electron transport chain (ETC) inhibition ("stress" test) informed respiratory and glycolytic parameters, respectively. Phorbol ester stimulation was used to trigger the oxidative burst. Basal OCR in all blood cell subtypes was similar in AP patients and controls. However, maximal respiration and spare respiratory capacity of AP patient lymphocytes were decreased, indicating impairment of functional capacity. A diminished oxidative burst occurred in neutrophils from AP patients, compared to controls, whereas this was enhanced in both monocytes and lymphocytes. The data demonstrate important early alterations of bioenergetics in blood cell sub-populations from AP patients, which imply functional alterations linked to clinical disease progression.

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Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice

Cited by 194 publications

References 58 publications

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation

Altered Bioenergetics of Blood Cell Sub-Populations in Acute Pancreatitis Patients

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