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

Ng, Benjamin; Widjaja, Anissa A.; Sivakumar, V.; Dong, Jinqiao; Chothani, Sonia; Lim, Si Ching; Shekeran, Shamini Guna; Tan, Jessie; Schäfer, Sebastian; Cook, Stuart A.

doi:10.1101/2020.12.10.420695

Cited by 7 publications

(9 citation statements)

References 23 publications

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“…Severe respiratory diseases such as IPF and SARS-COV-2 pneumonia are associated with defects in alveolar epithelial repair and irreversible loss of alveolar epithelial cells, which ultimately leads to fibrosis and a decline in lung function. We previously discovered an important role for IL11 in lung fibrosis, mediated via its profibrotic activity in lung fibroblasts and IL11 expression was confirmed in diseased fibroblasts in the current study ( 22, 25, 38 ). Here, we show that IL11 is specifically upregulated in aberrant alveolar epithelial cells in human PF and its expression is associated with pathological pro-EMT and inflammatory gene signatures in diseased epithelial cells.…”

Section: Discussionsupporting

confidence: 79%

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Huang

Pua

et al. 2022

Preprint

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Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGFbeta1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGFbeta1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion of Il11ra1 in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species.

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Section: Discussionsupporting

confidence: 79%

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Huang

Pua

et al. 2022

Preprint

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“…Although mice globally and germline deleted for Il11ra1 (30) are not protected from AILI (19), which we confirmed, we believe that this may, in part, be explained by off-target effects at the Il11ra1 locus, which we documented. Furthermore, there are unique features seen in the Il11ra1 KO mouse that are not apparent in Il11 null mice (31). Our studies advise caution against using a single genetic model on one genetic background for the study of AILI, and we suggest that loss-and gain-of-function approaches across genetic models are preferred, especially if complemented by specific pharmacologic interventions.…”

Section: Discussionmentioning

confidence: 83%

“…We recently found that, although Il11ra1 KO mice have similarities with a globally deleted Il11 mouse (Il11 KO), they also have differences in some phenotypes (31) and also in expression of Ccl27a (fig. S9, D and E).…”

Section: Mice Deleted For Il11 Are Protected From Ailimentioning

confidence: 99%

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury

et al. 2021

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Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)–dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

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“…39 Genetic LOF in IL11RA in mice and humans is associated with incompletely penetrant craniosynostosis and delayed tooth eruption but such mice and humans appear otherwise healthy with normal lifespans. 39–41 Furthermore, long-term administration of either anti-IL11 or anti-IL11RA to mice has not been associated with side effects. 27 With the right pharmacokinetic profile, antibody-based therapies can be administered subcutaneously monthly, even six-monthly, which may be acceptable regimen for the long-term administration of antibodies that inhibit IL11 signaling to patients with MFS.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL11 Signaling Reduces Aortic Pathology in Murine Marfan Syndrome

Lim

Dong

et al. 2022

Circulation Research

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Background: Marfan syndrome (MFS) is associated with TGF (transforming growth factor) β–stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFβ induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta. Methods: We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in Fbn1 C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11 EGFP/+ ) reporter strain or to a strain deleted for the IL11 receptor ( Il11ra1 −/− ). In therapeutic studies, mMFS were administered an X209 (neutralizing antibody against IL11RA [IL11 receptor subunit alpha]) or IgG for 20 weeks and imaged longitudinally. Results: IL11 mRNA and protein were elevated in the aortas of mMFS mice, as compared to controls. mMFS mice crossed to Il11 EGFP/+ mice had increased IL11 expression in VSMCs, notably in the aortic root and ascending aorta. As compared to the mMFS parental strain, double mutant mMFS: Il11ra1 −/ − mice had reduced aortic dilatation and exhibited lesser fibrosis, inflammation, elastin breaks, and VSMC loss, which was associated with reduced aortic COL1A1 (collagen type I alpha 1 chain), IL11, MMP2/9, and phospho-ERK expression. To explore therapeutic targeting of IL11 signaling in MFS, we administered either a neutralizing antibody against IL11RA (X209) or an IgG control. After 20 weeks of antibody administration, as compared to IgG, mMFS mice receiving X209 had reduced thoracic and abdominal aortic dilation as well as lesser fibrosis, inflammation, elastin breaks, and VSMC loss. By immunoblotting, X209 was shown to reduce aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression. Conclusions: In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.

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

Cited by 7 publications

References 23 publications

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury

Inhibition of IL11 Signaling Reduces Aortic Pathology in Murine Marfan Syndrome

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