2. Academic Validation
  3. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC

Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC

  • Nat Immunol. 2023 Aug 10. doi: 10.1038/s41590-023-01579-x.
John M Baer 1,  Chong Zuo 1,  Liang-I Kang 2,  Angela Alarcon de la Lastra 1,  Nicholas C Borcherding 2,  Brett L Knolhoff 1,  Savannah J Bogner 1,  Yu Zhu 1 3,  Liping Yang 4,  Jennifer Laurent 4,  Mark A Lewis 1 5,  Nan Zhang 2,  Ki-Wook Kim 2 6,  Ryan C Fields 2 7,  Wayne M Yokoyama 4,  Jason C Mills 5 8 9 10,  Li Ding 1 11 12 13,  Gwendalyn J Randolph 1 2,  David G DeNardo 14 15 16
Affiliations

Affiliations

  • 1 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Department of Pathology, Stanford University, Palo Alto, CA, USA.
  • 4 Division of Rheumatology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  • 5 Division of Gastroenterology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  • 6 Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, USA.
  • 7 Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
  • 8 Departments of Pathology and Immunology and Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  • 9 Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 10 Departments of Medicine, Pathology and Immunology, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 11 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 12 McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
  • 13 Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA.
  • 14 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. ddenardo@wustl.edu.
  • 15 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. ddenardo@wustl.edu.
  • 16 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. ddenardo@wustl.edu.
PMID: 37563309 DOI: 10.1038/s41590-023-01579-x
Abstract

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic Cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During 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.

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