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Nat Commun. 2017 Jul 24;8:16041. doi: 10.1038/ncomms16041.

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

Author information

1
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
2
Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, USA.
3
BioMedical Consultants, Marine on St. Croix, Minnesota 55047, USA.

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.

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