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Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically

Author

Listed:
  • Mingming Zhao

    (National Institutes of Health (NIH))

  • Dragana Jankovic

    (National Institutes of Health (NIH))

  • Verena M. Link

    (National Institutes of Health)

  • Camila Oliveira Silva Souza

    (National Institutes of Health (NIH))

  • Katherine M. Hornick

    (NIH)

  • Oyebola Oyesola

    (National Institutes of Health (NIH))

  • Yasmine Belkaid

    (National Institutes of Health)

  • Justin Lack

    (NIH)

  • Png Loke

    (National Institutes of Health (NIH))

Abstract

How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy 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.

Suggested Citation

  • Mingming Zhao & Dragana Jankovic & Verena M. Link & Camila Oliveira Silva Souza & Katherine M. Hornick & Oyebola Oyesola & Yasmine Belkaid & Justin Lack & Png Loke, 2025. "Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56379-8
    DOI: 10.1038/s41467-025-56379-8
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    References listed on IDEAS

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    1. Mingming Zhao & Jaimy Joy & Weiqiang Zhou & Supriyo De & William H Wood III & Kevin G Becker & Hongkai Ji & Ranjan Sen, 2018. "Transcriptional outcomes and kinetic patterning of gene expression in response to NF-κB activation," PLOS Biology, Public Library of Science, vol. 16(9), pages 1-33, September.
    2. Calum C. Bain & Catherine A. Hawley & Hannah Garner & Charlotte L. Scott & Anika Schridde & Nicholas J. Steers & Matthias Mack & Anagha Joshi & Martin Guilliams & Allan Mc I. Mowat & Frederic Geissman, 2016. "Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    3. S. Heinz & C. E. Romanoski & C. Benner & K. A. Allison & M. U. Kaikkonen & L. D. Orozco & C. K. Glass, 2013. "Effect of natural genetic variation on enhancer selection and function," Nature, Nature, vol. 503(7477), pages 487-492, November.
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