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

Inflammation after infectious or sterile traumatic insult and its subsequent resolution is a balanced process to combat pathogens and to induce tissue repair while avoiding aberrant inflammation induced organ damage. Macrophages are central players by participating in both inflammatory and repair processes and by skewing from a pro- to an anti-inflammatory repair phenotype. Glucocorticoids (GCs), which belong to the most active anti-inflammatory substances, were shown by the German team to be critically involved in macrophages to suppress inflammation in mouse models of contact allergy, experimental encephalomyelitis and septic shock. Furthermore they show that in a model of acute lung injury the combined action of the GC receptor (GR) and the MAP kinase p38 results in the induction of an anti-inflammatory marker gene necessary to resolve lung inflammation. By this they identified a novel mechanism how GCs suppress inflammation. Strikingly similar are anti-inflammatory activities of the fuel-sensing enzyme 5'AMP-activated protein kinase (AMPK). Absence of AMPK increases pro-inflammatory cytokine expression, whereas AMPK activation induces the expression of anti-inflammatory markers. The French group demonstrated that AMPK activation is required for a proper repair of damaged muscle by inducing an anti-inflammatory phenotype in macrophages. Common preliminary work now provide evidence that i) GCs influence muscle repair dependent on AMPK in vitro, that ii) anti-inflammatory effects of GCs is lost in AMPK-deficient macrophages and that iii) AMPK-phosphorylation is enhanced by GCs. We therefore hypothesize that GR and AMPK act in concert and mutually interact to achieve their anti-inflammatory properties in macrophages, essential to resolve inflammation and to induce tissue repair. We will characterize the crosstalk of AMPK and GR activation in macrophages during immune challenges and tissue repair by using conditional GR and AMPK mutant mice exposed to GR and AMPK activators. We will determine how GR and AMPK in concert regulate inflammatory mediators and control the dynamics to adopt anti-inflammatory macrophage phenotype. We will address in an acute lung inflammation model (non sterile inflammation) and in a muscle repair model (sterile inflammation) how AMPK contributes to the therapeutic actions of GCs and vice versa. We will further exploit a potential cooperative activity of GCs and AMPK activators as a possibility to reduce GC dosage and thus to avoid side effects of GC therapy. We expect from this integrative project insights into the interference of AMPK and GR signaling as a novel paradigm of immune suppression, which could give the base for new rationales to improve steroid therapies and tissue repair.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Bénédicte Chazaud, Ph.D.