Natural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival

Konrad Buscher, Erik Ehinger, Pritha Gupta, Akula Bala Pramod, Dennis Wolf, George Tweet, Calvin Pan, Charles D. Mills, Aldons J. Lusis and Klaus Ley ()
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Konrad Buscher: La Jolla Institute for Allergy and Immunology
Erik Ehinger: La Jolla Institute for Allergy and Immunology
Pritha Gupta: Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California
Akula Bala Pramod: La Jolla Institute for Allergy and Immunology
Dennis Wolf: La Jolla Institute for Allergy and Immunology
George Tweet: La Jolla Institute for Allergy and Immunology
Calvin Pan: Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California
Charles D. Mills: BioMedical Consultants
Aldons J. Lusis: Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California
Klaus Ley: La Jolla Institute for Allergy and Immunology

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12β and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings.

Date: 2017
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DOI: 10.1038/ncomms16041

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