Il11-KO Mouse

Interleukin 11 (IL11), a cytokine of the IL6 family, was initially thought to be a haematopoietic and cytoprotective factor. However, recent data suggest it has more complex functions. It signals via pathways such as JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine, playing a role in processes like mesenchymal transition of various cell types after tissue injury [2].

In mouse models, deletion of Il11 or Il11ra1 has shown significant impacts. In acute kidney injury, Il11 deletion or treatment with a neutralizing IL11 antibody prevents SNAI1 expression and kidney dysfunction, while anti-TGFβ treatment only reduces fibrosis but exacerbates other pathologies [1]. In a chronic kidney disease model, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration [1]. In AOM/DSS-induced tumor models, Il11 knockout increases CD8+ T cell infiltration and reduces intestinal and colon tumor formation, as IL11/STAT3 signaling downregulates MHC-I and CXCL9 [3]. Deletion of Il11 in mice also protects against metabolic decline, multi-morbidity and frailty in old age, and extends lifespan [4].

In conclusion, IL11 is involved in inflammation, fibrosis, and tissue repair processes. Mouse models with Il11 or Il11ra1 deletion have revealed its role in kidney diseases, colitis-associated cancers, and age-related pathologies, highlighting IL11 as a potential therapeutic target for these disease areas.

References:

1. 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/

2. Cook, Stuart A. . Understanding interleukin 11 as a disease gene and therapeutic target. In The Biochemical journal, 480, 1987-2008. doi:10.1042/BCJ20220160. https://pubmed.ncbi.nlm.nih.gov/38054591/

3. Xiong, Wenjun, Chen, Yuehong, Zhang, Chaoting, Shi, Zhimin, Mou, Tingyu. 2023. Pharmacologic inhibition of IL11/STAT3 signaling increases MHC-I expression and T cell infiltration. In Journal of translational medicine, 21, 416. doi:10.1186/s12967-023-04079-6. https://pubmed.ncbi.nlm.nih.gov/37365574/

4. 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/