Fgr-KO Mouse

Fgr, a member of the Src family of tyrosine kinases, is involved in multiple biological processes. It participates in the innate immune response, and is associated with hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. It may also interact with other molecules and signaling pathways to regulate various cellular functions [1,2].

In a cecal ligation and puncture (CLP)-induced mouse sepsis model, CLP-induced sepsis increased the expression of Fgr in hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, improved the survival rate, alleviated cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Fgr interacted with SIRT1 and reduced its activity and expression. Activation of the SIRT1/PGC-1α pathway promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation counteracted these benefits [1]. In another study, inhibition of tyrosine kinase Fgr prevented radiation-induced pulmonary fibrosis (RIPF) in mice. Senescent cells from the lungs of mice with RIPF release profibrotic proteins, and the Fgr inhibitor TL02-59 reduced the release of these profibrotic chemokines without reducing the number of senescent cells. In thoracic-irradiated mice, TL02-59 also prevented RIPF, reduced fibrotic gene products, and decreased the recruitment of CD11b+ macrophages to the lungs [3].

In conclusion, Fgr is a key tyrosine kinase involved in the innate immune response and has implications in diseases such as sepsis-associated encephalopathy and radiation-induced pulmonary fibrosis. Studies using mouse models, including through pharmacological inhibition (functionally similar to loss-of-function in vivo), have revealed its role in regulating neuroinflammation, mitochondrial function, and fibrosis, providing potential therapeutic targets for these disease areas.

References:

1. Liu, Yuqiang, Yang, Han, Luo, Nanbo, Yu, Buwei, Liu, Zhiheng. 2023. An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway. In Journal of translational medicine, 21, 486. doi:10.1186/s12967-023-04345-7. https://pubmed.ncbi.nlm.nih.gov/37475042/

2. Patel, M, Faulkner, L, Katz, D R, Brickell, P M. . The c-fgr proto-oncogene: expression in Epstein-Barr-virus-infected B lymphocytes and in cells of the myelomonocytic and granulocytic lineages. In Pathobiology : journal of immunopathology, molecular and cellular biology, 59, 289-92. doi:. https://pubmed.ncbi.nlm.nih.gov/1652975/

3. Mukherjee, Amitava, Epperly, Michael W, Fisher, Renee, Wipf, Peter, Greenberger, Joel S. 2023. Inhibition of tyrosine kinase Fgr prevents radiation-induced pulmonary fibrosis (RIPF). In Cell death discovery, 9, 252. doi:10.1038/s41420-023-01538-3. https://pubmed.ncbi.nlm.nih.gov/37460469/