AP-1 transcription factors roles in the control of macrophage polarization
Parasitology and Biology of Tropical Infectious Disease Pathogens
Rheumatology
Final Report Abstract
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, Mφ can express a large spectrum of activation statuses ranging from classically activated Mφ (M1 Mφ) to the alternatively activated Mφ (M2 Mφ). While substantial information on the role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) exist in Mφ functions, we have uncovered new roles of AP-1 transcription factor in this context. We have discovered an important role of Fra-1 for the functional reprogramming of macrophages. Analyses of the K/BxN arthritis mouse model and of tissue sections of patients with active or inactive RA revealed an inverse correlation between Fra-1 and Arg1. Fra-1 directly suppressed Arg1 gene transcription and thereby altered macrophage responses, which impeded the resolution of inflammation. Moreover, we could also show that FRA-1 and lipocalin 2 (cn2) were positively correlated in response to LPS, both in tolerant murine and human macrophage in vitro. Using ChIP-seq and ChIP-qPCR, FRA-1 was shown to bind Lcn2 promoter, especially in the tolerant state. Finally, in vivo septic model using consecutive injection of LPS showed a decreased resolution as well as an increased inflammation in FRA-1 depleted conditions, likely dependent on the low level of Lcn 2 in these mice. Collectively, our results indicate that FRA-1 transcription factor is involved in myeloid cell tolerant responses by mediating the functional reprogramming of Lcn2 transcription is sepsis responses.
Publications
- (2017). "The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages." The Journal of Immunology 198(9): 3605-3614
Hannemann, N., et al.
(See online at https://doi.org/10.4049/jimmunol.1601330) - (2018) Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin. Mol Cell Biol. 2018 Oct 29;38(22)
Luo Y, et al.
(See online at https://doi.org/10.1128/mcb.00022-18) - (2019). "Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis." The Journal of Clinical Investigation 129(7): 2669-2684
Hannemann, N., et al.
(See online at https://doi.org/10.1172/jci96832) - (2020). Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b. Cell Death Differ
Chen, G. L. et al.
(See online at https://doi.org/10.1038/s41418-020-00660-4) - (2021). "The Transcription Factor FRA-1/AP-1 Controls Lipocalin-2 Expression and Inflammation in Sepsis Model." Frontiers in Immunology 12
Cao, S., et al.
(See online at https://doi.org/10.3389/fimmu.2021.701675)
