Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis
Identifieur interne : 000038 ( Pmc/Curation ); précédent : 000037; suivant : 000039Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis
Auteurs : Moritz Leppkes [Allemagne] ; Christian Maueröder [Allemagne] ; Sebastian Hirth [Allemagne] ; Stefanie Nowecki [Allemagne] ; Claudia Günther [Allemagne] ; Ulrike Billmeier [Allemagne] ; Susanne Paulus [Allemagne] ; Mona Biermann [Allemagne] ; Luis E. Munoz [Allemagne] ; Markus Hoffmann [Allemagne] ; Dane Wildner [Allemagne] ; Andrew L. Croxford [Allemagne] ; Ari Waisman [Allemagne] ; Kerri Mowen [États-Unis] ; Dieter E. Jenne [Allemagne] ; Veit Krenn [Allemagne] ; Julia Mayerle [Allemagne] ; Markus M. Lerch [Allemagne] ; Georg Schett [Allemagne] ; Stefan Wirtz [Allemagne] ; Markus F. Neurath [Allemagne] ; Martin Herrmann [Allemagne] ; Christoph Becker [Allemagne]Source :
- Nature Communications [ 2041-1723 ] ; 2016.
Abstract
Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.
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DOI: 10.1038/ncomms10973
PubMed: 26964500
PubMed Central: 4793047
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Jenne</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Institute of Lung Biology and Disease, Comprehensive Pneumology Center</institution>, 81377 Munich,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Krenn, Veit" sort="Krenn, Veit" uniqKey="Krenn V" first="Veit" last="Krenn">Veit Krenn</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pathology, MVZ of Pathology</institution>, 54296 Trier,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mayerle, Julia" sort="Mayerle, Julia" uniqKey="Mayerle J" first="Julia" last="Mayerle">Julia Mayerle</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Medicine A, University Medicine Greifswald</institution>, 17475 Greifswald,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lerch, Markus M" sort="Lerch, Markus M" uniqKey="Lerch M" first="Markus M." last="Lerch">Markus M. 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pancreatitis</title><author><name sortKey="Leppkes, Moritz" sort="Leppkes, Moritz" uniqKey="Leppkes M" first="Moritz" last="Leppkes">Moritz Leppkes</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Maueroder, Christian" sort="Maueroder, Christian" uniqKey="Maueroder C" first="Christian" last="Maueröder">Christian Maueröder</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hirth, Sebastian" sort="Hirth, Sebastian" uniqKey="Hirth S" first="Sebastian" last="Hirth">Sebastian Hirth</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University</institution>, 55131 Mainz,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nowecki, Stefanie" sort="Nowecki, Stefanie" uniqKey="Nowecki S" first="Stefanie" last="Nowecki">Stefanie Nowecki</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gunther, Claudia" sort="Gunther, Claudia" uniqKey="Gunther C" first="Claudia" last="Günther">Claudia Günther</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Billmeier, Ulrike" sort="Billmeier, Ulrike" uniqKey="Billmeier U" first="Ulrike" last="Billmeier">Ulrike Billmeier</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Paulus, Susanne" sort="Paulus, Susanne" uniqKey="Paulus S" first="Susanne" last="Paulus">Susanne Paulus</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Biermann, Mona" sort="Biermann, Mona" uniqKey="Biermann M" first="Mona" last="Biermann">Mona Biermann</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Munoz, Luis E" sort="Munoz, Luis E" uniqKey="Munoz L" first="Luis E." last="Munoz">Luis E. Munoz</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hoffmann, Markus" sort="Hoffmann, Markus" uniqKey="Hoffmann M" first="Markus" last="Hoffmann">Markus Hoffmann</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wildner, Dane" sort="Wildner, Dane" uniqKey="Wildner D" first="Dane" last="Wildner">Dane Wildner</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Croxford, Andrew L" sort="Croxford, Andrew L" uniqKey="Croxford A" first="Andrew L." last="Croxford">Andrew L. Croxford</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University</institution>, 55131 Mainz,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Waisman, Ari" sort="Waisman, Ari" uniqKey="Waisman A" first="Ari" last="Waisman">Ari Waisman</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University</institution>, 55131 Mainz,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mowen, Kerri" sort="Mowen, Kerri" uniqKey="Mowen K" first="Kerri" last="Mowen">Kerri Mowen</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Chemical Physiology, Scripps Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Immunology and Microbial Sciences, Scripps Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jenne, Dieter E" sort="Jenne, Dieter E" uniqKey="Jenne D" first="Dieter E." last="Jenne">Dieter E. Jenne</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Institute of Lung Biology and Disease, Comprehensive Pneumology Center</institution>, 81377 Munich,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Krenn, Veit" sort="Krenn, Veit" uniqKey="Krenn V" first="Veit" last="Krenn">Veit Krenn</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pathology, MVZ of Pathology</institution>, 54296 Trier,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mayerle, Julia" sort="Mayerle, Julia" uniqKey="Mayerle J" first="Julia" last="Mayerle">Julia Mayerle</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Medicine A, University Medicine Greifswald</institution>, 17475 Greifswald,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lerch, Markus M" sort="Lerch, Markus M" uniqKey="Lerch M" first="Markus M." last="Lerch">Markus M. Lerch</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Medicine A, University Medicine Greifswald</institution>, 17475 Greifswald,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Schett, Georg" sort="Schett, Georg" uniqKey="Schett G" first="Georg" last="Schett">Georg Schett</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wirtz, Stefan" sort="Wirtz, Stefan" uniqKey="Wirtz S" first="Stefan" last="Wirtz">Stefan Wirtz</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Neurath, Markus F" sort="Neurath, Markus F" uniqKey="Neurath M" first="Markus F." last="Neurath">Markus F. Neurath</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Herrmann, Martin" sort="Herrmann, Martin" uniqKey="Herrmann M" first="Martin" last="Herrmann">Martin Herrmann</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Becker, Christoph" sort="Becker, Christoph" uniqKey="Becker C" first="Christoph" last="Becker">Christoph Becker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Ductal occlusion has been postulated to precipitate focal pancreatic inflammation,
while the nature of the primary occluding agents has remained elusive. Neutrophils
make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in
contact to particulate agents to extrude decondensed chromatin as neutrophil
extracellular traps (NETs). In high cellular density, NETs form macroscopically
visible aggregates. Here we show that such aggregates form inside pancreatic ducts
in humans and mice occluding pancreatic ducts and thereby driving pancreatic
inflammation. Experimental models indicate that PADI4 is critical for intraductal
aggregate formation and that PADI4-deficiency abrogates disease progression.
Mechanistically, we identify the pancreatic juice as a strong instigator of
neutrophil chromatin extrusion. Characteristic single components of pancreatic
juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated
NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with
relevance in a plethora of inflammatory conditions involving secretory ducts.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lankisch, P G" uniqKey="Lankisch P">P. G. Lankisch</name></author><author><name sortKey="Apte, M" uniqKey="Apte M">M. Apte</name></author><author><name sortKey="Banks, P A" uniqKey="Banks P">P. A. Banks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lerch, M M" uniqKey="Lerch M">M. M. Lerch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guy, O" uniqKey="Guy O">O. Guy</name></author><author><name sortKey="Robles Diaz, G" uniqKey="Robles Diaz G">G. Robles-Diaz</name></author><author><name sortKey="Adrich, Z" uniqKey="Adrich Z">Z. Adrich</name></author><author><name sortKey="Sahel, J" uniqKey="Sahel J">J. Sahel</name></author><author><name sortKey="Sarles, H" uniqKey="Sarles H">H. Sarles</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Freedman, S D" uniqKey="Freedman S">S. D. Freedman</name></author><author><name sortKey="Sakamoto, K" uniqKey="Sakamoto K">K. Sakamoto</name></author><author><name sortKey="Venu, R P" uniqKey="Venu R">R. P. Venu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haruta, I" uniqKey="Haruta I">I. Haruta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Etemad, B" uniqKey="Etemad B">B. Etemad</name></author><author><name sortKey="Whitcomb, D C" uniqKey="Whitcomb D">D. C. Whitcomb</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Braganza, J M" uniqKey="Braganza J">J. M. Braganza</name></author><author><name sortKey="Lee, S H" uniqKey="Lee S">S. H. Lee</name></author><author><name sortKey="Mccloy, R X0a F" uniqKey="Mccloy R">R.
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26964500</article-id><article-id pub-id-type="pmc">4793047</article-id><article-id pub-id-type="pii">ncomms10973</article-id><article-id pub-id-type="doi">10.1038/ncomms10973</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives
pancreatitis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Leppkes</surname><given-names>Moritz</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Maueröder</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hirth</surname><given-names>Sebastian</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Nowecki</surname><given-names>Stefanie</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Günther</surname><given-names>Claudia</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Billmeier</surname><given-names>Ulrike</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Paulus</surname><given-names>Susanne</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Biermann</surname><given-names>Mona</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Munoz</surname><given-names>Luis E.</given-names></name><xref ref-type="aff" rid="a2">2</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-5395-804X</contrib-id></contrib><contrib contrib-type="author"><name><surname>Hoffmann</surname><given-names>Markus</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wildner</surname><given-names>Dane</given-names></name><xref ref-type="aff" rid="a1">1</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4916-6533</contrib-id></contrib><contrib contrib-type="author"><name><surname>Croxford</surname><given-names>Andrew L.</given-names></name><xref ref-type="aff" rid="a3">3</xref><xref ref-type="author-notes" rid="n2">†</xref></contrib><contrib contrib-type="author"><name><surname>Waisman</surname><given-names>Ari</given-names></name><xref ref-type="aff" rid="a3">3</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4304-8234</contrib-id></contrib><contrib contrib-type="author"><name><surname>Mowen</surname><given-names>Kerri</given-names></name><xref ref-type="aff" rid="a4">4</xref><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Jenne</surname><given-names>Dieter E.</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Krenn</surname><given-names>Veit</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Mayerle</surname><given-names>Julia</given-names></name><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Lerch</surname><given-names>Markus M.</given-names></name><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Schett</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wirtz</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Neurath</surname><given-names>Markus F.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Herrmann</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Becker</surname><given-names>Christoph</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><aff id="a1"><label>1</label><institution>Department of Medicine 1, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></aff><aff id="a2"><label>2</label><institution>Department of Medicine 3, University Clinics Erlangen, University of Erlangen-Nuremberg</institution>, 91054 Erlangen,<country>Germany</country></aff><aff id="a3"><label>3</label><institution>Institute of Molecular Medicine, University Medicine of Johannes Gutenberg University</institution>, 55131 Mainz,<country>Germany</country></aff><aff id="a4"><label>4</label><institution>Department of Chemical Physiology, Scripps Institute</institution>, La Jolla, California 92037,<country>USA</country></aff><aff id="a5"><label>5</label><institution>Department of Immunology and Microbial Sciences, Scripps Institute</institution>, La Jolla, California 92037,<country>USA</country></aff><aff id="a6"><label>6</label><institution>Institute of Lung Biology and Disease, Comprehensive Pneumology Center</institution>, 81377 Munich,<country>Germany</country></aff><aff id="a7"><label>7</label><institution>Department of Pathology, MVZ of Pathology</institution>, 54296 Trier,<country>Germany</country></aff><aff id="a8"><label>8</label><institution>Department of Medicine A, University Medicine Greifswald</institution>, 17475 Greifswald,<country>Germany</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>moritz.leppkes@uk-erlangen.de</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work</p></fn><fn id="n2"><label>†</label><p>Present address: Department of Neuroimmunology, University of Zurich, 8057
Zurich, Switzerland</p></fn></author-notes><pub-date pub-type="epub"><day>11</day><month>03</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>10973</elocation-id><history><date date-type="received"><day>06</day><month>07</month><year>2015</year></date><date date-type="accepted"><day>08</day><month>02</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights
Reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights
Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this article are
included in the article's Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the Creative
Commons license, users will need to obtain permission from the license holder to
reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Ductal occlusion has been postulated to precipitate focal pancreatic inflammation,
while the nature of the primary occluding agents has remained elusive. Neutrophils
make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in
contact to particulate agents to extrude decondensed chromatin as neutrophil
extracellular traps (NETs). In high cellular density, NETs form macroscopically
visible aggregates. Here we show that such aggregates form inside pancreatic ducts
in humans and mice occluding pancreatic ducts and thereby driving pancreatic
inflammation. Experimental models indicate that PADI4 is critical for intraductal
aggregate formation and that PADI4-deficiency abrogates disease progression.
Mechanistically, we identify the pancreatic juice as a strong instigator of
neutrophil chromatin extrusion. Characteristic single components of pancreatic
juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated
NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with
relevance in a plethora of inflammatory conditions involving secretory ducts.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms10973-i1.jpg"></inline-graphic>Pancreatitis often develops as a consequence of ductal obstruction.
Here, the authors show that bicarbonate ions initiate the release of neutrophil
extracellular traps (NETs) that form pancreatic ductal aggregates and occlude the ducts,
thereby driving pancreatitis in mice and humans.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Delivery of IL-17A induces pancreatitis with intraductal neutrophils.</title><p>(<bold>a</bold>,<bold>b</bold>) Haematoxylin and eosin staining of tissue sections
obtained from human chronic pancreatitis (<bold>a</bold>), malignancy-related
pancreatic inflammation (<bold>b</bold>) and murine pancreatitis induced by IL-17A
delivery. (specific features are marked in the lower picture: +,
fatty degeneration; §, fibrotic stroma; *, pseudotubular
complex; dotted line and arrow, healthy area). (<bold>a</bold>) Note the focal
nature of the disease with remodelled adjacent to intact glandular tissue
(representative of <italic>n</italic>=13 (human) and <italic>n</italic>⩾15
(mouse); bar, 500 μm); (<bold>b</bold>) note cell-containing
aggregates (coloured) inside pancreatic ducts (grey scale) in murine (15/15)
and human samples (0/5 benign chronic pancreatitis, 3/8 malignancy
associated). (<bold>c</bold>) Top: cells with segmented nuclei inside intraductal
aggregates in human pancreatitis showed dual labelling for MPO and IL-17A
(3/3); bottom: a close-up shows IL-17A immunoreactivity in a human
granulocyte with a typical segmented nucleus (bar, 5 μm).
(<bold>d</bold>) In IL-17A-induced pancreatitis,
IL-17A<sup>+</sup>MPO<sup>+</sup> aggregates
were observed in the lumen of acini and ducts. No MPO- or IL-17A-positive
cells were observed in control tissue (<italic>n</italic>=4 per group).
(<bold>e</bold>) Note wasting in IL-17A-treated mice (<italic>n</italic>=8
per group, mean+s.e.m.). (<bold>f</bold>) Analysis by flow cytometry of
bone marrow and spleen cells demonstrated IL-17A-enforced granulopoesis and
neutrophil mobilization (<italic>n</italic>⩾15 per group). (<bold>g</bold>) Luminol
bioluminescence imaging showed MPO activity in the upper abdomen of
IL-17A-treated mice only, projected on the mesenteric part of the pancreas
(<italic>n</italic>=4 per group; bars, 1 cm). (<bold>h</bold>)
Tryptic activity of pancreas homogenates was fluorometrically assessed and
showed a significant increase after IL-17A delivery as compared with control
(two independent experiments, <italic>n</italic>=6 per group).
(<bold>i</bold>,<bold>j</bold>) Analyses at day 10 and day 28 after IL-17A delivery
demonstrated leukocyte infiltration at day 10, diminishing over time and a
progressive remodelling of the pancreas. The control vector does not induce
morphologic changes (<italic>n</italic>⩾8 per time point and group).
(<bold>i</bold>) Immunohistochemistry reveals infiltration of neutrophils and
macrophages into the pancreas 10 days after IL-17A delivery
(<italic>n</italic>⩾10 per group). MPO<sup>+</sup> cells displays
patchy aggregation. After 28 days, MPO<sup>+</sup> aggregates
were found inside a pancreatic duct and in the periductal area. The
aggregates are negative for F4/80, which is confined to myeloid cells
throughout the fibroinflammatory stroma. Black scale bars,
200 μm; white scale bars, 50 μm, unless
stated otherwise. (*<italic>P</italic><0.05,
***<italic>P</italic><0.001, Student's
<italic>t</italic>-test).</p></caption><graphic xlink:href="ncomms10973-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>IL-17A-induced pancreatitis is driven by PADI4-dependent neutrophil
aggregates.</title><p>(<bold>a</bold>) Ly6G immunohistochemistry detected neutrophil granulocyte
aggregates in the pancreas after IL-17A challenge only. (<bold>b</bold>,<bold>c</bold>)
Mice treated with IL-17A delivery or control were injected with a
neutrophil-depleting anti-Ly6G antibody (1A8) or isotype control (2A3)
(three independent experiments with <italic>n</italic>=12 per group,
***<italic>P</italic><0.001 (analysis of variance,
Tukey honest significant difference). (<bold>b</bold>) Haematoxylin and eosin
(H&E) staining (top) and MPO immunofluorescence (bottom) showed that
IL-17A-induced pancreatitis depends on Ly6G<sup>+</sup>granulocytes. (<bold>c</bold>) The area subject to fibroinflammatory remodelling
was strongly reduced by anti-Ly6G treatment. The isotype antibody was
without protective effect. (mean+s.e.m.). (<bold>d</bold>) A close-up of
an aggregate after IL-17A delivery displayed neutrophils bound together by
amorphous haematoxylin-stained fibres (day 28; top left).
4,6-Diamidino-2-phenylindole (DAPI) staining revealed DNA configured in
non-nuclear morphology inside these ducts (bottom left).
Immunohistochemistry of citrullinated histone H3 (H3cit) was detected on
extracellular DNA (centre, right: staining control). (<bold>e</bold>) EpCAM/H3cit
co-staining revealed aggregates formed in pancreatic ducts and metaplastic
acini (day 10 after IL-17A delivery). Co-staining of neutrophil elastase
(ELANE), Cramp and H3cit showed ELANE and Cramp on intraductal aggregates
with PADI4 activity, even in areas, in which extracellular DNA was below
detection level. The cellular density of intact neutrophils inside
aggregates was increased at day 10 as compared with day 28, precluding a
closer examination of non-nuclear DNA. H3cit was also detectable inside
granulocyte nuclei at this time point. (<bold>f</bold>) Thioglycolate-elicited
neutrophils from wild-type and PADI4<sup>−/−</sup>mice were stimulated with lipopolysaccharide
(100 ng ml<sup>−1</sup>), and
chromatin morphology was determined by Sytox Green fluorescence. Wild-type
cells showed an increased size of the area covered by DNA and bizarrely
configured DNA tangles, reflecting chromatin decondensation. Chromatin
appeared more condensed in PADI4<sup>−/−</sup>neutrophils (>3 independent experiments).
(<bold>g</bold>–<bold>i</bold>) Wild-type and
PADI4<sup>−/−</sup> mice were treated with
IL-17A or a mock control vector. (<bold>g</bold>) H&E-staining revealed no
pancreatitis development in PADI4<sup>−/−</sup> mice
in response to IL-17A. (<bold>h</bold>) MPO and ELANE immunohistochemistry showed
only few MPO<sup>+</sup> or ELANE<sup>+</sup>cells in the pancreata of PADI4<sup>−/−</sup>IL-17A-challenged mice. In wild-type controls, patchy neutrophil
accumulation was noted all-over the section (two independent experiments
with a total of <italic>n</italic>⩾12 per group. (<bold>i</bold>) The area affected
by fibroinflammatory remodelling was strongly diminished in
PADI4<sup>−/−</sup> mice (mean+s.e.m.;
black scale bars, 200 μm; white scale bars,
50 μm, unless stated otherwise.
***<italic>P</italic><0.001, Student's
<italic>t</italic>-test).</p></caption><graphic xlink:href="ncomms10973-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Components of pancreatic juice facilitate externalization of decondensed
neutrophil chromatin.</title><p>(<bold>a</bold>) Immunofluorescence of myeloperoxidase (MPO) and citrullinated
histone H3 (H3cit) revealed intraductal neutrophil aggregates in human
pancreatic inflammation (immunopositivity rates of samples:
malignancy-related pancreatitis (3/8) and benign chronic (0/5) pancreatitis,
respectively); single channels are provided to appreciate low-intensity
extracellular DNA between intact neutrophils. (<bold>b</bold>) Intraductal
aggregates display CD66b<sup>+</sup> cells and co-labelling of
H3cit and extracellular DNA (3/3). (<bold>c</bold>) Cytospins from fresh
patient-derived pancreatic fluid punctates of patients with benign
pancreatitis revealed DNA webs positive for (left) neutrophil elastase
(ELANE) and (right) H3cit with the respective staining control (right
column; <italic>n</italic>=3/3). (<bold>d</bold>,<bold>e</bold>) Freshly isolated human
blood neutrophils were cultured in human pancreatic juice or isotonic
HBSS-based buffers containing varying amounts of NaHCO<sub>3</sub>, as
indicated. DNA in the cell culture was quantified with a Sytox Green
fluorimetric assay detecting extracellular DNA and chromatin of
permeabilized cells only (DNA<sup>SYTOX</sup>). (<bold>d</bold>) Quantitative
assessment indicated strong increases in DNA<sup>SYTOX</sup> of human
neutrophil cultures in response to human pancreatic juice
(<italic>n</italic>=20; 3 h of stimulation). (<bold>e</bold>)
NaHCO<sub>3</sub> dose dependently raises DNA<sup>SYTOX</sup> as
compared with NaHCO<sub>3</sub>-free conditions. This effect was facilitated
by ambient pCO<sub>2</sub> levels. Five percent of CO<sub>2</sub> was able
to inhibit DNA detection induced by 10 mM NaHCO<sub>3</sub>, yet
failed to inhibit DNA detection at higher concentrations of
NaHCO<sub>3</sub> (50 mM; <italic>n</italic>=3 independent
experiments, mean+s.e.m.). (<bold>f</bold>) Freshly isolated human blood
neutrophils grown on coverslips developed decondensed chromatin and
aggregates positive for (left) neutrophil elastase and citrullinated
histones (right) in response to calcium carbonate crystals
(5 mg ml<sup>−1</sup>, ⩾4
independent experiments). (All white scale bars, 50 μm.
*<italic>P</italic><0.05, **<italic>P</italic><0.01,
***<italic>P</italic><0.001, Student's
<italic>t</italic>-test.)</p></caption><graphic xlink:href="ncomms10973-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>NaHCO<sub>3</sub>-induced cellular changes support PADI4 activity.</title><p>(<bold>a</bold>) Freshly isolated human neutrophils from the peripheral blood of
healthy donors were cultured on glass coverslips for 120 min at
37 °C/5% CO<sub>2</sub> and subjected to
isotonic HBSS media containing different concentrations of
HCO<sub>3</sub><sup>−</sup>. The calculated pH equilibrium
of the bicarbonate–CO<sub>2</sub> buffer system of these media at
37 °C/5% CO<sub>2</sub> is specified.
Immunocytochemistry of H3cit (top) and neutrophil elastase (bottom), and the
respective DNA<sup>SYTOX</sup> counterstain in both overlay as well as
single-channel analyses are provided. Please note the absence of
H3cit<sup>+</sup> ELANE<sup>+</sup>extracellular chromatin in the absence of NaHCO<sub>3</sub>. The presence of
NaHCO<sub>3</sub> in the media leads to marked increases in
H3cit<sup>+</sup> ELANE<sup>+</sup>extracellular chromatin reminiscent of NETs (representative pictures of one
of three independent experiments are shown). (<bold>b</bold>) Ratiometric
determination of the cytosolic Ca<sup>2+</sup> concentration
revealed the elevation of
[Ca<sup>2+</sup>]<sub>I</sub> induced by
75 mM NaHCO<sub>3</sub> (<italic>n</italic>=4 independent
experiments). (<bold>c</bold>) The intracellular pH of human neutrophils was
measured by flow cytometry employing SNARF as pH-sensitive dye under ambient
pCO<sub>2</sub>. Note the time- and bicarbonate-concentration-dependent
increase of the cytoplasmic pH (<italic>n</italic>=3 independent
experiments, mean+s.e.m.). (<bold>d</bold>) Chromatin externalization by
50 mM bicarbonate was induced in human granulocytes from healthy
donors in the presence or absence of the PADI inhibitor Cl-amidine
(1 mM) and images of propidium iodide fluorescence as in <xref ref-type="supplementary-material" rid="S1">Supplementary Fig. 8H</xref> were
morphometrically analysed. The nuclear decondensation is reflected by an
increased ratio of chromatin area to mean fluorescence intensity (MFI) in
flow cytometry. The data are normalized to 100 for an average healthy
nucleus. Note the nuclear decondensation induced by bicarbonate, which was
reduced in the presence of Cl-amidine (⩾3 independent experiments).
(All white scale bars, 50 μm.
*<italic>P</italic><0.05, **<italic>P</italic><0.01,
***<italic>P</italic><0.001, Student's
<italic>t</italic>-test).</p></caption><graphic xlink:href="ncomms10973-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Intraductal formation of carbonate-induced aggNETs causes segmental
pancreatic atrophy.</title><p>(<bold>a</bold>–<bold>c</bold>) Neutrophil-rich peritonitis was induced in mice
by means of intraperitoneal thioglycolate injection. After 18 h,
2 ml of 150 mM sodium bicarbonate, calcium carbonate
crystals (20 mg) or 2 ml of saline control were
injected into the peritoneal cavity. Thirty minutes later, a peritoneal HBSS
lavage was aspirated, aggregates were collected and processed for
consecutive immunocytochemistry; (<bold>a</bold>) note that aggNETs visible to the
naked eye could only be aspirated after injection of NaHCO<sub>3</sub> but
not in saline control (<bold>b</bold>). Carbonate-induced aggNETs formed <italic>in
vivo</italic> were immunopositive for citrullinated histone H3 and neutrophil
elastase (ELANE) (three independent experiments of a total of
<italic>n</italic>=6 per group). (<bold>c</bold>) Model of the aggNET transfer
technique. We carefully transferred calcium carbonate crystals
(0.5 mg) and thioglycolate-induced neutrophils
(10<sup>6</sup> cells) in 10 μl each to the
biliopancreatic duct to form aggNETs <italic>in situ</italic>, as well as saline or
single-component controls. The biliary duct was ligated with a suture close
to the liver hilus. (<bold>d</bold>) Intraoperative situs post aggNET transfer.
The biliopancreatic duct filled with aggNETs and the stomach are marked by
arrows and asterisks, respectively (bar, 10 mm). (<bold>e</bold>)
Pancreatic duct filled with an aggregate after <italic>in situ</italic> aggNET
formation (bar, 100 μm). (<bold>f</bold>) Immunohistochemical
detection of citrullinated histone and myeloperoxidase in intraductal
aggNETs 4 h after aggNET transfer. (<bold>g</bold>) Haematoxylin and
eosin staining and (<bold>i</bold>) vimentin immunohistochemistry revealed the
marked segmental fibroinflammatory area and mesenchymal cell expansion 6
days after aggNET transfer. (<bold>h</bold>) The sectional area of the pancreas
affected by fibroinflammatory remodelling 6 days after aggNET transfer was
calculated for each experimental group (two independent experiments,
<italic>n</italic>=6 per group, mean+s.e.m.,
**<italic>P</italic><0.01 one-way analysis of
variance/<italic>post hoc</italic> Tukey honest significant difference analysis).
(<bold>j</bold>–<bold>l</bold>) Crystals and neutrophil preparations of
PADI4-deficient and wild-type mice were placed in biliopancreatic ducts of
the respective recipients of the same genotype (two independent experiments,
<italic>n</italic>=9 per group, **<italic>P</italic><0.01
Student's <italic>t</italic>-test). In both experimental groups,
fibroinflammatory remodelling was evident (<bold>j</bold>), yet the affected
fibroinflammatory area was markedly reduced in PADI4-deficient mice
(mean+s.e.m.) (<bold>k</bold>). Mesenchymal expansion as assessed by
vimentin immunohistochemistry was attenuated as compared with wild-type
controls (<bold>l</bold>). Black scale bars, 200 μm; white scale
bars, 50 μm, unless stated otherwise.</p></caption><graphic xlink:href="ncomms10973-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Model of neutrophil-mediated ductal occlusion.</title><p>Model of intrapancreatic intraductal neutrophil accumulation in response to
IL-17A and its downstream targets followed by increased intraductal
chromatin extrusion and aggregation in response to
HCO<sub>3</sub><sup>−</sup> leading to microocclusion on
the acinar level (left) or macroocclusion on the lobular ductal level
(right).</p></caption><graphic xlink:href="ncomms10973-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Hypothesis chart.</title><p>Danger signals, exemplified by IL-17A challenge, instigate enforced
granulopoesis, neutrophil mobilization and increased chemoattraction to the
pancreas. When neutrophils encounter stimuli in the pancreatic juice such as
elevated bicarbonate levels or CaCO<sub>3</sub> precipitations, they form
aggNETs. The large chromatin tangles of the latter reduce the fluidity of
the pancreatic juice and consequently hamper secretory flow and lead to
focal occlusion of the ductal tree. In occluded areas, digestive zymogens
undergo premature activation. AggNET-borne serine proteases in static fluid
may amplify this process. Dependent acini are destroyed, inflammation is
perpetuated and finally tissue remodelling ensues.</p></caption><graphic xlink:href="ncomms10973-f7"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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