The BACH1-HMOX1 regulatory axis is indispensable for proper macrophage subtype specification and skeletal muscle regeneration

Andreas Patsalos, Petros Tzerpos, Laszlo Halasz, Gergely Nagy, Attila Pap, Nikolas Giannakis, Konstantina Lyroni, Vasiliki Koliaraki, Eva Pintye, Balazs Dezso, George Kollias, Charalampos G. Spilianakis, Laszlo Nagy

Research output: Contribution to journalArticle

Abstract

The infiltration and subsequent in situ subtype specification of monocytes to effector/inflammatory and repair macrophages is indispensable for tissue repair upon acute sterile injury. However, the chromatin-level mediators and regulatory events controlling this highly dynamic macrophage phenotype switch are not known. In this study, we used a murine acute muscle injury model to assess global chromatin accessibility and gene expression dynamics in infiltrating macrophages during sterile physiological inflammation and tissue regeneration. We identified a heme-binding transcriptional repressor, BACH1, as a novel regulator of this process. Bach1 knockout mice displayed impaired muscle regeneration, altered dynamics of the macrophage phenotype transition, and transcriptional deregulation of key inflammatory and repair-related genes. We also found that BACH1 directly binds to and regulates distal regulatory elements of these genes, suggesting a novel role for BACH1 in controlling a broad spectrum of the repair response genes in macrophages upon injury. Inactivation of heme oxygenase-1 (Hmox1), one of the most stringently deregulated genes in the Bach1 knockout in macrophages, impairs muscle regeneration by changing the dynamics of the macrophage phenotype switch. Collectively, our data suggest the existence of a heme-BACH1-HMOX1 regulatory axis, that controls the phenotype and function of the infiltrating myeloid cells upon tissue damage, shaping the overall tissue repair kinetics.

Original languageEnglish (US)
Pages (from-to)1532-1547
Number of pages16
JournalJournal of Immunology
Volume203
Issue number6
DOIs
StatePublished - Sep 15 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Patsalos, A., Tzerpos, P., Halasz, L., Nagy, G., Pap, A., Giannakis, N., Lyroni, K., Koliaraki, V., Pintye, E., Dezso, B., Kollias, G., Spilianakis, C. G., & Nagy, L. (2019). The BACH1-HMOX1 regulatory axis is indispensable for proper macrophage subtype specification and skeletal muscle regeneration. Journal of Immunology, 203(6), 1532-1547. https://doi.org/10.4049/jimmunol.1900553