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Early trypsin activation develops independently of autophagy in caerulein-induced pancreatitis in mice

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Abstract

Premature intrapancreatic trypsinogen activation is widely regarded as an initiating event for acute pancreatitis. Previous studies have alternatively implicated secretory vesicles, endosomes, lysosomes, or autophagosomes/autophagolysosomes as the primary site of trypsinogen activation, from which a cell-damaging proteolytic cascade originates. To identify the subcellular compartment of initial trypsinogen activation we performed a time-resolution analysis of the first 12 h of caerulein-induced pancreatitis in transgenic light chain 3 (LC3)-GFP autophagy reporter mice. Intrapancreatic trypsin activity increased within 60 min and serum amylase within 2 h, but fluorescent autophagosome formation only by 4 h of pancreatitis in parallel with a shift from cytosolic LC3-I to membranous LC3-II on Western blots. At 60 min, activated trypsin in heavier subcellular fractions was co-distributed with cathepsin B, but not with the autophagy markers LC3 or autophagy protein 16 (ATG16). Supramaximal caerulein stimulation of primary pancreatic acini derived from LC3-GFP mice revealed that trypsinogen activation is independent of autophagolysosome formation already during the first 15 min of exposure to caerulein. Co-localization studies (with GFP-LC3 autophagosomes versus Ile–Pro–Arg–AMC trypsin activity and immunogold-labelling of lysosomal-associated membrane protein 2 [LAMP-2] versus trypsinogen activation peptide [TAP]) indicated active trypsin in autophagolysosomes only at the later timepoints. In conclusion, during the initiating phase of caerulein-induced pancreatitis, premature protease activation develops independently of autophagolysosome formation and in vesicles arising from the secretory pathway. However, autophagy is likely to regulate overall intracellular trypsin activity during the later stages of this disease.

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Abbreviations

Em:

Emission

Ex:

Excitation

AMC:

7-Amido 4-methylcoumarin

MAP-LC3:

Microtubule-associated protein 1-light chain 3

GFP:

Green fluorescent protein

FITC:

Fluorescein isothiocyanate

h:

Hour

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Funding

This work was supported by the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-D2/E3/E4, GRK1947-A3, MA 4115/1-2/3, AG 203/2-1, SE 2702/2-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03IS2061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012) and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1, TBI-V-1-083-VBW-028, PePPP center of excellence MV ESF/14-BM-A55-0045/16; ESF MV V-630-S-150-2012/132/133),). FSG and AG are supported by Veterans Administration Merit Awards.

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Author notes

  1. Markus M. Lerch and Julia Mayerle equally contributed to the study.

  2. Walter Halangk passed away on August 20th 2018. This manuscript is dedicated to his memory.

Authors and Affiliations

  1. Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, 17475, Germany

    Sudarshan R. Malla, Matthias Sendler, Ujjwal M. Mahajan, F. Ulrich Weiss, Franziska G. Thiel, Ali A. Aghdassi, Markus M. Lerch & Julia Mayerle

  2. Division of Medical Biology, University of Rostock, Rostock, 18051, Germany

    Burkhard Krueger

  3. Division of Experimental Surgery, University of Magdeburg, Magdeburg, 39120, Germany

    Thomas Wartmann, Carina De Boni & Walter Halangk

  4. Yale University Medical School, New Haven, CT, 06510, USA

    Fred S. Gorelick

  5. Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, 79104, Germany

    Thomas Reinheckel

  6. Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine, Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis, University of California at Los Angeles, Los Angeles, CA, 90073, USA

    Sudarshan R. Malla & Anna S. Gukovskaya

  7. Department of Medicine II, Ludwigs-Maximilians University Munich, 80539, Munich, Germany

    Ujjwal M. Mahajan & Julia Mayerle

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  1. Sudarshan R. Malla
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Contributions

SRM, BK, TW, MS, UMM, FGT, and CDB were involved in data acquisition, analysis, and interpretation of data, and drafting and revision of the manuscript. FUW, FSG, WH, TR, AA, and AG were involved in critical analysis of data, interpretation, and manuscript revision; JM, SRM, WH, TR, and MML: study concept and design, drafting of the manuscript, and obtained funding, study supervision.

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Correspondence to Markus M. Lerch.

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Malla, S.R., Krueger, B., Wartmann, T. et al. Early trypsin activation develops independently of autophagy in caerulein-induced pancreatitis in mice. Cell. Mol. Life Sci. 77, 1811–1825 (2020). https://doi.org/10.1007/s00018-019-03254-7

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