Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Abstract

Abstract

Genetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11^-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11^-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11^-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11^-/- female mice are infertile. Unlike Il11ra1^-/- mice, Il11^-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

Competing Interest Statement

S.A.C. and S. S. are co-inventors of the patent applications (WO2017103108, WO2017103108 A2, WO 2018/109174 A2, WO 2018/109170 A2) for Treatment of fibrosis. A.A.W., S. S. and S.A.C. are co-inventors of the patent applications (GB1900811.9, GB 1902419.9, GB1906597.8) for Treatment of hepatotoxicity, nephrotoxicity, and metabolic diseases. S. S., S. A.C. and B.N. are co-inventors of the patent application (WO/2019/073057) for Treatment of SMC mediated disease. S.A.C. and S.S. are co-founders and shareholders of Enleofen Bio PTE LTD. All other co-authors declare no competing interests.