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Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC

John M. Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C. Borcherding, Brett L. Knolhoff, Savannah J. Bogner, Yu Zhu, Mark A. Lewis, Nan Zhang, Ki-Wook Kim, Ryan C. Fields, Jason C. Mills, Li Ding, Gwendalyn J. Randolph, David G. DeNardo
doi: https://doi.org/10.1101/2022.02.09.479745
John M. Baer
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Chong Zuo
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Liang-I Kang
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Angela Alarcon de la Lastra
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Nicholas C. Borcherding
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Brett L. Knolhoff
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Savannah J. Bogner
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Yu Zhu
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
5Department of Pathology, Stanford University, Palo Alto, CA, 94304, USA
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Mark A. Lewis
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
7Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
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Nan Zhang
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Ki-Wook Kim
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
6Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL
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Ryan C. Fields
3Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Jason C. Mills
7Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
8Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
9Departments of Pathology and Immunology and Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
10Departments of Medicine, Pathology and Immunology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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Li Ding
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
2Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
11McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63110, USA
12Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA
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Gwendalyn J. Randolph
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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David G. DeNardo
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
2Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
4Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • For correspondence: ddenardo@wustl.edu
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Summary

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages (MDMs). However, whether TRMs and MDMs have functional distinction under differing pathologies is not understood. Here, we show a significant portion of macrophages that accumulated during pancreatitis and pancreatic cancer were expanded from TRMs. We further established that pancreas TRMs have a distinct extracellular matrix remodeling phenotype that was critical for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and animal death, due to impaired acinar cell survival and recovery. In pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 10, 2022.
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Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC
John M. Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C. Borcherding, Brett L. Knolhoff, Savannah J. Bogner, Yu Zhu, Mark A. Lewis, Nan Zhang, Ki-Wook Kim, Ryan C. Fields, Jason C. Mills, Li Ding, Gwendalyn J. Randolph, David G. DeNardo
bioRxiv 2022.02.09.479745; doi: https://doi.org/10.1101/2022.02.09.479745
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Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC
John M. Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C. Borcherding, Brett L. Knolhoff, Savannah J. Bogner, Yu Zhu, Mark A. Lewis, Nan Zhang, Ki-Wook Kim, Ryan C. Fields, Jason C. Mills, Li Ding, Gwendalyn J. Randolph, David G. DeNardo
bioRxiv 2022.02.09.479745; doi: https://doi.org/10.1101/2022.02.09.479745

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