Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer
- Oregon Health & Science University, United States
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
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The transcriptional profile of neutrophils in different organs during pancreatic cancerNCBI Gene Expression Omnibus, GSE150061.
Article and author information
Author details
Kevin Glenn Burfeind
Katherine A Michaelis
Eileen Ruth Samson Torres
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.
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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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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