Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer

Abstract

Weight loss and anorexia are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. Pharmacologic CCR2 blockade and genetic deletion of Ccr2 both resulted in significantly decreased brain-infiltrating myeloid cells as well as attenuated cachexia during PDAC. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished immune cell recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Sequencing data have been deposited in GEO under accession code GSE15006

The following data sets were generated

Article and author information

Author details

  1. Kevin Glenn Burfeind

    Pediatrics, Oregon Health & Science University, Portland, United States
    For correspondence
    burfeind@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4192-6753
  2. Xinxia Zhu

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mason Andrew Norgard

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Peter Robert Levasseur

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christian Huisman

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Abigail C Buenafe

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brennan Olson

    Pediatrics, MD/PhD Program, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Katherine A Michaelis

    Pediatrics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3225-3649
  9. Eileen Ruth Samson Torres

    Behavioral Neuroscience, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5340-8734
  10. Sophia Jeng

    Biostatistics, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Shannon McWeeney

    Biostatistics, Knight Cancer Institute, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jacob Raber

    Behavioral Neuroscience, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9861-9893
  13. Daniel L Marks

    Pediatrics, Oregon Health & Science University, Portland, United States
    For correspondence
    marksd@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2675-7047

Funding

National Cancer Institute (R01CA184324-01)

  • Daniel L Marks

National Cancer Institute (R01CA217989-01)

  • Daniel L Marks

Brenden-Colson Center for Pancreatic Care

  • Daniel L Marks

National Cancer Institute (5F30CA213745)

  • Kevin Glenn Burfeind

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Oregon Health & Science University. The protocol was approved by the Department of Comparative Medicine of Oregon Health & Science University (protocol IP00038). All surgery was performed under isofluorane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Yuting Ma, Suzhou Institute of Systems Medicine, China

Publication history

  1. Received: December 2, 2019
  2. Accepted: April 21, 2020
  3. Accepted Manuscript published: May 11, 2020 (version 1)
  4. Version of Record published: May 26, 2020 (version 2)

Copyright

© 2020, Burfeind et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kevin Glenn Burfeind
  2. Xinxia Zhu
  3. Mason Andrew Norgard
  4. Peter Robert Levasseur
  5. Christian Huisman
  6. Abigail C Buenafe
  7. Brennan Olson
  8. Katherine A Michaelis
  9. Eileen Ruth Samson Torres
  10. Sophia Jeng
  11. Shannon McWeeney
  12. Jacob Raber
  13. Daniel L Marks
(2020)
Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer
eLife 9:e54095.
https://doi.org/10.7554/eLife.54095

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