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

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 (PD...

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Bibliographic Details
Published in:	eLife Vol. 9
Main Authors:	Burfeind, Kevin G, Zhu, Xinxia, Norgard, Mason A, Levasseur, Peter R, Huisman, Christian, Buenafe, Abigail C, Olson, Brennan, Michaelis, Katherine A, Torres, Eileen Rs, Jeng, Sophia, McWeeney, Shannon, Raber, Jacob, Marks, Daniel L
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 11-05-2020 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Subjects:	Adenocarcinoma Analysis Animals Anorexia Anorexia - etiology Brain Brain - physiopathology Brain tumors Cachexia Cachexia - etiology Cancer Cancer cells Cancer treatment Carcinoma, Pancreatic Ductal - complications Carcinoma, Pancreatic Ductal - pathology CC chemokine receptors CCR2 protein Central nervous system Chemokine CCL2 - genetics Chemokine CCL2 - metabolism Chemokines Clinical trials Cytokines Disease Models, Animal Diseases Experiments Fatigue Female Flow cytometry Genetically modified organisms Health aspects Heart failure Hypothalamus Immune response Immune system Immunology and Inflammation Inflammation Leukocytes (neutrophilic) Lung diseases Male Malignancy Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Monocyte chemoattractant protein 1 Myeloid cells Myeloid Cells - immunology Myeloid Cells - metabolism neuroimmunology Neuroscience Neutrophil Infiltration neutrophils Neutrophils - metabolism Pancreatic cancer Pancreatic Neoplasms - complications Pancreatic Neoplasms - pathology Receptors, CCR2 - genetics Receptors, CCR2 - metabolism Respiratory tract diseases Weight Loss mouse neuroimmunology pancreatic cancer myeloid cells inflammation neuroscience cachexia brain immunology neutrophils
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Summary:	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 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.54095