TY - JOUR
T1 - The BACH1-HMOX1 regulatory axis is indispensable for proper macrophage subtype specification and skeletal muscle regeneration
AU - Patsalos, Andreas
AU - Tzerpos, Petros
AU - Halasz, Laszlo
AU - Nagy, Gergely
AU - Pap, Attila
AU - Giannakis, Nikolas
AU - Lyroni, Konstantina
AU - Koliaraki, Vasiliki
AU - Pintye, Eva
AU - Dezso, Balazs
AU - Kollias, George
AU - Spilianakis, Charalampos G.
AU - Nagy, Laszlo
N1 - Funding Information:
A. Patsalos, P.T., and L.N. are supported by "Nuclear Receptor-Network" Consortium Grant PITN-GA-2013-606806 from the European Union Seventh Framework Programme Marie Curie Initial Training Network and as part of the PEOPLE-2013 program. G.N. is supported by a grant from the Hungarian Scientific Research Fund (OTKA PD124843). N.G. and L.N. are supported by the "Chromatin3D" Innovative Training Network funded by the European Union under the Horizon-2020 Framework Programme (Grant Agreement 622934) and a grant from the Higher Education Institutional Excellence Programme (20428-3/2018/FEKUTSTRAT) of the Ministry of Human Capacities. L.N. is also supported by grants from the Hungarian Scientific Research Fund (Grants K124298, KH126885, and KKP129909) and by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115924).
Funding Information:
A. Patsalos, P.T., and L.N. are supported by “Nuclear Receptor-Network” Consortium Grant PITN-GA-2013-606806 from the European Union Seventh Framework Programme Marie Curie Initial Training Network and as part of the PEOPLE-2013 program. G.N. is supported by a grant from the Hungarian Scientific Research Fund (OTKA PD124843). N.G. and L.N. are supported by the “Chromatin3D” Innovative Training Network funded by the European Union under the Horizon-2020 Framework Programme (Grant Agreement 622934) and a grant from the Higher Education Institutional Excellence Programme (20428-3/2018/FEKUTSTRAT) of the Ministry of Human Capacities. L.N. is also supported by grants from the Hungarian Scientific Research Fund (Grants K124298, KH126885, and KKP129909) and by the National Institutes of
Publisher Copyright:
Copyright © 2019 by The American Association of Immunologists, Inc.
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1900553
DO - 10.4049/jimmunol.1900553
M3 - Article
C2 - 31405954
AN - SCOPUS:85071995063
SN - 0022-1767
VL - 203
SP - 1532
EP - 1547
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -