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

Konrad Buscher,Charles D Mills,Pritha Gupta,George Tweet,Calvin Pan,Aldons J Lusis,Akula Bala Pramod,Dennis Wolf,Klaus Ley,Erik Ehinger

doi:10.1038/ncomms16041

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.

Highlights

Mouse models exist for many immune-based diseases, the clinical translation remains challenging
LPS is found in gram-negative bacterial membranes and elicits strong inflammatory immune responses, mainly via Toll-like receptor (TLR) 4 that induces activation of the NF-kB pathway[35]
In human alveolar macrophages exposed to LPS in vivo we observed large intrinsic variation in inter-individual genetic responses, for example, NF-kB and TLR pathway activities (Fig. 1a,b)

Summary

Introduction

Mouse models exist for many immune-based diseases, the clinical translation remains challenging. 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. The hybrid mouse diversity panel (HMDP) is a panel of about 100 inbred mouse strains developed for performing association studies with adequate statistical power and resolution for mapping of complex traits[30,31] It has been successfully used for investigating gene-environment interaction in activated macrophages[32], insulin sensitivity[33], and susceptibility to atherosclerosis[34]. We employ the HMDP as a surrogate model for human immune diversity and investigate how meaningful gene signatures of macrophage activation can be extracted from a heterogeneous population We demonstrate that these signatures are highly robust in predicting disease susceptibility and outcomes in humans, suggesting that immune diversity is a critical parameter in translational medicine

Methods

Results

Conclusion