2. Academic Validation
  3. Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver

Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver

  • Cell. 2019 Aug 22;178(5):1205-1221.e17. doi: 10.1016/j.cell.2019.07.017.
Saurav Roy Choudhury 1,  Liane Babes 2,  Jennifer J Rahn 1,  Bo-Young Ahn 1,  Kimberly-Ann R Goring 1,  Jennifer C King 1,  Arthur Lau 3,  Björn Petri 4,  Xiaoguang Hao 1,  Andrew K Chojnacki 3,  Ajitha Thanabalasuriar 3,  Erin F McAvoy 3,  Sébastien Tabariès 5,  Christoph Schraeder 6,  Kamala D Patel 7,  Peter M Siegel 5,  Karen A Kopciuk 8,  David C Schriemer 6,  Daniel A Muruve 9,  Margaret M Kelly 10,  Bryan G Yipp 11,  Paul Kubes 7,  Stephen M Robbins 12,  Donna L Senger 13
Affiliations

Affiliations

  • 1 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 2 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 3 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 4 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Snyder Institute for Chronic Diseases Mouse Phenomics Resource Laboratory, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 5 Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
  • 6 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 7 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 8 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB T2S 3C3, Canada.
  • 9 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 10 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 11 Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 12 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • 13 Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: [email protected].
PMID: 31442408 DOI: 10.1016/j.cell.2019.07.017
Abstract

A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.

Keywords

ALI; acute lung injury; adhesion receptor; cell adhesion; dipeptidase-1 (DPEP1); endothelium; endotoxemia; intravital imaging; lung vasculature; neutrophil recruitment; sepsis.

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