# Genetic variation in IL-4 activated tissue resident macrophages alters the epigenetic state to determine strain specific synergistic responses to LPS

## TL;DR

Genetic differences between mouse strains affect how macrophages respond to IL-4 and LPS, leading to distinct immune responses.

## Contribution

The study reveals how genetic variation alters epigenetic reprogramming in macrophages, causing strain-specific immune responses.

## Key findings

- C57BL/6 macrophages show greater transcriptional and epigenetic responses to IL-4 compared to BALB/c.
- IL-4-activated C57BL/6 macrophages exhibit enhanced synergy with LPS compared to BALB/c.
- Transcriptional differences and synergy are cell-intrinsic, as shown by chimeric mouse experiments.

## Abstract

How macrophages in the tissue environment integrate multiple stimuli will depend on the genetic background of the host, but this is poorly understood. Here, we investigated C57BL/6 and BALB/c strain specific in vivo IL-4 activation of tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with a greater association of induced genes with super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling revealed BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated BL/6 TRMs demonstrated an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure compared to BALB/c TRMs, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS than naïve BL/6 TRMs. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeric mice indicated that transcriptional differences between BL/6 and BALB/c TRMs, and synergy between IL-4 and LPS, are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.