Τίτλος:
The BACH1-HMOX1 regulatory axis is indispensable for proper macrophage subtype specification and skeletal muscle regeneration
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. Copyright © 2019 by The American Association of Immunologists, Inc.
Συγγραφείς:
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.
Περιοδικό:
Journal of Immunological Methods
Εκδότης:
American Association of Immunologists
Λέξεις-κλειδιά:
heme oxygenase 1; protein BACH1; transcription factor; unclassified drug; Bach1 protein, mouse; basic leucine zipper transcription factor; heme oxygenase 1; Hmox1 protein, mouse; membrane protein, animal cell; animal experiment; animal model; animal tissue; Article; Bach1 gene; controlled study; gene; gene expression; Hmox1 gene; inflammation; macrophage; male; mouse; muscle injury; muscle regeneration; nonhuman; priority journal; protein binding; regulatory sequence; skeletal muscle; transcription regulation; animal; C57BL mouse; genetic transcription; knockout mouse; macrophage; metabolism; phenotype; physiology; regeneration; skeletal muscle, Animals; Basic-Leucine Zipper Transcription Factors; Heme Oxygenase-1; Inflammation; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Phenotype; Regeneration; Transcription, Genetic
DOI:
10.4049/jimmunol.1900553
