GR-AMPK - Crosstalk of Glucocorticoid Receptor and AMP-induced Kinase in macrophages during inflammation and tissue repair

• Applicant: Professor Dr. Jan Tuckermann
• Subject Area: Immunology ; Endocrinology, Diabetology, Metabolism
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283865434

• Final Report Year: 2021

Final Report Abstract

Resolution of inflammation is an essential process to limit inflammation upon inflammatory insult to return to tissue homeostasis and to induce repair processes. Glucocorticoids (GCs) are the most frequently prescribed anti-inflammatory agents mediate their actions through macrophages in many inflammatory diseases. Macrophages are essential regulators of the resolution of inflammation, but the mechanisms by which GCs act on macrophages are viewed as a merely repression of inflammatory mediator cytokines by the GC receptor (GR). The induction of anti-inflammatory and regenerative phenotypes of macrophages by GCs is surprisingly, poorly characterized. We have previously shown that the metabolic regulator AMPK is required for the resolution of inflammation by macrophages. In this exciting collaborative project, funded by DFG and ANR, we show that GCs exert their antiinflammatory effects on macrophages through the activation of AMPK. AMPK activation is required for the shift from pro- to anti-inflammatory profile of macrophages driven by GC treatment in vitro and in vivo in a model of tissue injury (skeletal muscle regeneration) and of systemic inflammation (acute lung injury). As a result, animals deficient for AMPKa1 in myeloid cells are unresponsive to GC treatment in either model. Surprisingly, repression of cytokines or induction of anti-inflammatory genes were not altered at the absence of AMPK and thus not sufficient to overcome the failure to resolve inflammation by glucocorticoids. We further discovered an anti-inflammatory acting axis by GCs AMPK and the transcription factor Foxo3 to mediate anti-inflammatory function in macrophages. We are convinced that this work makes a significant advance in the understanding of immunosuppression by GCs and of macrophage biology, and provides an important link between cellular metabolism and inflammation. Our project enhanced our understanding of the active process of resolution of inflammation evoked by hormones such as cortisol.

Publications

• (2017) Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity. Cell Metab 26, 620-632 e626
  Quarta C, Clemmensen C, Zhu Z, Yang B, Joseph SS, Lutter D, Yi CX, Graf E, Garcia- Caceres C, Legutko B, … Tuckermann J, et al.
  
• (2018) Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice. J Clin Invest 128, 3265-3279
  Ballegeer M, Van Looveren K, Timmermans S, Eggermont M, Vandevyver S, Thery F, Dendoncker K, Souffriau J, Vandewalle J, Van Wyngene, L, …, Tuckermann J, et al.
  
• (2019) A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology. Front Immunol 10, 2460
  Ahmad M, Hachemi Y, Paxian K, Mengele F, Koenen M, Tuckermann J
  
• (2019) A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling. FASEB J 33, 5924-5941
  Glantschnig C, Koenen M, Gil-Lozano M, Karbiener M, Pickrahn I, Williams-Dautovich J, Patel R, Cummins CL, Giroud M, Hartleben G, … Tuckermann J, et al.
  
• (2019) Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor. Front Immunol 10, 1859
  Escoter-Torres L, Caratti G, Mechtidou A, Uhlenhaut NH, Vettorazzi S
  
• (2019) Glucocorticoids Shape Macrophage Phenotype for Tissue Repair. Front Immunol 10, 1591
  Desgeorges T, Caratti G, Mounier R, Tuckermann J, Chazaud B
  
• (2020) AMPKα1 is essential for Glucocorticoid Receptor triggered antiinflammatory macrophage activation
  Caratti G, Desgeorges T, Juban G, Koenen M, Kozak B, Theret M, Chazaud B, Tuckermann J, Mounier R