AP-1 transcription factors roles in the control of macrophage polarization

• Applicant: Professorin Dr. Aline Bozec, Ph.D.
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Rheumatology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387043890

Macrophages play pivotal roles in the innate and adaptive immune system. On one side, they are essential for the uptake, killing and degradation of pathogens and for the processing and presentation of antigens. On the other side, they are crucial for the termination of inflammatory processes and the restoration of tissue homeostasis. To fulfil all these functions, macrophages can express a large spectrum of activation statuses ranging from classically activated macrophages (M1 macrophages) to the alternatively activated macrophages (M2 macrophages). While substantial information on the role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) exist in macrophage functions, few is known about the role of AP-1 transcription factor in this context.Our project aims to determine how the AP-1 transcription factor family regulates macrophage activation. Since Fra proteins are the least AP-1 members studied, we will have a particular interest on the role of Fra-1 and Fra-2 proteins in macrophages. First, we will characterize in vitro how Fra-1 or Fra-2 deletion affects the response of macrophages to different stimuli covering from pro-inflammatory, mild stimulatory or anti-inflammatory responses in macrophages. In addition to these canonical polarisation stimuli, the function of the Fra proteins will also be addressed in infections with Listeria monocytogenes (L.m.) to unravel their impact on the crucial anti-microbial activity of macrophages. A computational network analysis will be performed for the different stimuli using RNA sequencing and ChIP sequencing to get unbiased results of Fra dependent activation. To transfer our finding in vivo, we will study the genetically engineered mouse models for Fra-1 or Fra-2 deleted specifically in the myeloid lineage. Two murine disease models, listeriosis and rheumatoid arthritis will be used, allowing us to characterize the importance of Fra proteins in macrophages during acute or chronic inflammatory processes.The long term aim of our research is to define whether modulation of macrophage polarization is suitable to terminate the inflammatory processes and to restore the tissue homeostasis.

• DFG Programme: Research Grants