Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-11, Vol.45 (5), p.1038-1051
• Main Authors: Varga, Tamas, Mounier, Rémi, Patsalos, Andreas, Gogolák, Péter, Peloquin, Matthew, Horvath, Attila, Pap, Attila, Daniel, Bence, Nagy, Gergely, Pintye, Eva, Poliska, Szilárd, Cuvellier, Sylvain, Ben Larbi, Sabrina, Sansbury, Brian E., Spite, Matthew, Brown, Chester W., Chazaud, Bénédicte, Nagy, Laszlo
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Separation; Chromatin Immunoprecipitation; Disease Models, Animal; Gene Expression Regulation - physiology; Growth Differentiation Factor 3 - metabolism; Mice; Mice, Inbred C57BL; Muscle, Skeletal - injuries; Muscle, Skeletal - physiology; Myoblasts - metabolism; Oligonucleotide Array Sequence Analysis; PPAR gamma - metabolism; Regeneration - physiology; Wound Healing - physiology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.10.016

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. [Display omitted] •Macrophage PPARγ is required for skeletal muscle regeneration•PPARγ regulates GDF3 in muscle infiltrating Ly6C− repair macrophages•The Gdf3 locus has multiple PPARγ:RXR heterodimer-bound active enhancers•GDF3 regulates muscle regeneration and enhances primary myoblast fusion PPARγ is a lipid activated transcription factor essential for fat cells and linked to lipid processing in macrophages. Varga et al. (2016) now show that PPARγ is transcriptionally active and regulates the growth factor Gdf3 in repair macrophages in regenerating skeletal muscle, forming a paracrine axis connecting macrophages to muscle progenitor fusion.