Il11ra1-KO Mouse

Il11ra1, the interleukin 11 receptor subunit alpha-1, is crucial for IL-11 signaling. IL-11, a pro-inflammatory cytokine of the IL-6 family, regulates an ERK-AMPK-mTORC1 axis, and Il11ra1 is essential for the cytokine to exert its effects on this axis, which is associated with cellular, tissue-and organismal-level ageing pathologies [1].

In various mouse models, genetic deletion of Il11ra1 has shown protective effects. In aged mice, it protects against metabolic decline, multi-morbidity, and frailty [1]. In models of cardiac fibrosis, it inhibits macrophage-to-myofibroblast transition and subsequent cardiac fibrosis and dysfunction [2]. In fibrotic diseases, such as idiopathic pulmonary fibrosis, Il11ra1-deleted mice, with unresponsive lung fibroblasts to profibrotic stimulation, are protected from fibrosis [3]. In non-alcoholic steatohepatitis (NASH) models, Il11ra1-deficient mice have reduced steatosis, fibrosis, and inflammation [4,5]. In acute and chronic kidney disease models, TEC-specific deletion of Il11ra1 reduces pathogenic signaling and protects from renal injury-induced inflammation, fibrosis, and failure [6]. In acetaminophen-induced liver injury, hepatocyte-specific deletion of Il11ra1 protects against liver injury [7].

In summary, Il11ra1 is essential for IL-11-mediated signaling. Model-based research, especially through Il11ra1 knockout mouse models, has revealed its significant role in multiple disease areas including ageing-related pathologies, fibrosis in different organs, NASH, and liver injury. These findings suggest that targeting Il11ra1 could be a potential therapeutic strategy for these diseases.

References:

1. Widjaja, Anissa A, Lim, Wei-Wen, Viswanathan, Sivakumar, Carling, David, Cook, Stuart A. 2024. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. In Nature, 632, 157-165. doi:10.1038/s41586-024-07701-9. https://pubmed.ncbi.nlm.nih.gov/39020175/

2. Zhuang, Tao, Chen, Mei-Hua, Wu, Ruo-Xi, Zuo, Jun-Li, Ruan, Cheng-Chao. 2024. ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice. In Nature communications, 15, 1995. doi:10.1038/s41467-024-46357-x. https://pubmed.ncbi.nlm.nih.gov/38443404/

3. Ng, Benjamin, Dong, Jinrui, D'Agostino, Giuseppe, Schafer, Sebastian, Cook, Stuart A. . Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. In Science translational medicine, 11, . doi:10.1126/scitranslmed.aaw1237. https://pubmed.ncbi.nlm.nih.gov/31554736/

4. Widjaja, Anissa A, Singh, Brijesh K, Adami, Eleonora, Schafer, Sebastian, Cook, Stuart A. 2019. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. In Gastroenterology, 157, 777-792.e14. doi:10.1053/j.gastro.2019.05.002. https://pubmed.ncbi.nlm.nih.gov/31078624/

5. Dong, Jinrui, Viswanathan, Sivakumar, Adami, Eleonora, Cook, Stuart A, Widjaja, Anissa A. 2021. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. In Nature communications, 12, 66. doi:10.1038/s41467-020-20303-z. https://pubmed.ncbi.nlm.nih.gov/33397952/

6. Widjaja, Anissa A, Viswanathan, Sivakumar, Shekeran, Shamini G, Coffman, Thomas M, Cook, Stuart A. 2022. Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease. In Nature communications, 13, 7497. doi:10.1038/s41467-022-35306-1. https://pubmed.ncbi.nlm.nih.gov/36470928/

7. Widjaja, Anissa A, Dong, Jinrui, Adami, Eleonora, Schafer, Sebastian, Cook, Stuart A. . Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. In Science translational medicine, 13, . doi:10.1126/scitranslmed.aba8146. https://pubmed.ncbi.nlm.nih.gov/34108253/