Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration.
Tissue regeneration requires inflammatory and reparatory activity of macrophages. Macrophages detect and eliminate the damaged tissue and subsequently promote regeneration. This dichotomy requires the switch of effector functions of macrophages coordinated with other cell types inside the injured tissue. The gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here we show that the lipid activated transcription factor, PPARγ, is required for proper skeletal muscle regeneration, acting in repair macrophages. PPARγ controls the expression of the transforming growth factor-β (TGF-β) family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by promoting muscle progenitor cell fusion. This work establishes PPARγ as a required metabolic sensor and transcriptional regulator of repair macrophages. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as an exclusively macrophage-derived regeneration factor in tissue repair.
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.
Tamas
T
Varga
Institut NeuroMyogène, INMG, Université Claude Bernard Lyon 1, CNRS UMR5310, Villeurbanne 69100, INSERM U1217, France.
Rémi
R
Mounier
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.
Andreas
A
Patsalos
Department of Immunology, University of Debrecen, Debrecen, H-4012, Hungary.
Péter
P
Gogolák
Sanford-Burnham-Prebys Medical Discovery Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827.
Matthew
M
Peloquin
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.
Attila
A
Horvath
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.
Attila
A
Pap
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.|Sanford-Burnham-Prebys Medical Discovery Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827.
Bence
B
Daniel
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.|MTA-DE "Lendület" Immunogenomics Research Group, University of Debrecen, Debrecen, H-4012, Hungary.
Gergely
G
Nagy
Department of Radiation Therapy, University of Debrecen, Debrecen, H-4012, Hungary.
Eva
E
Pintye
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.
Szilárd
S
Póliska
Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
Sylvain
S
Cuvellier
Institut NeuroMyogène, INMG, Université Claude Bernard Lyon 1, CNRS UMR5310, Villeurbanne 69100, INSERM U1217, France.
Sabrina Ben
SB
Larbi
Center for Experimental Therapeutics & Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115.
Brian E
BE
Sansbury
Center for Experimental Therapeutics & Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115.
Matthew
M
Spite
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.|Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.|Texas Children's Hospital, Houston, TX 77030.
Chester W
CW
Brown
Institut NeuroMyogène, INMG, Université Claude Bernard Lyon 1, CNRS UMR5310, Villeurbanne 69100, INSERM U1217, France.|Institut Cochin, INSERM U1016, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
Bénédicte
B
Chazaud
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4012, Hungary.|Sanford-Burnham-Prebys Medical Discovery Institute at Lake Nona, 6400 Sanger Road, Orlando, FL 32827.|MTA-DE "Lendület" Immunogenomics Research Group, University of Debrecen, Debrecen, H-4012, Hungary.
Laszlo
L
Nagy
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D055451:Growth Differentiation Factor 3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries / Q000502:physiology*; D032446:Myoblasts / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology
C525975:Gdf3 protein, mouse; D055451:Growth Differentiation Factor 3; D047495:PPAR gamma