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; McGregor, Narelle E; Walker, Emma C; Sims, Natalie A; Schäfer, Sebastian; Cook, Stuart A.

doi:10.1038/s41598-021-93623-9

Cited by 28 publications

(24 citation statements)

References 34 publications

(64 reference statements)

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“…Hematopoietic cell lineage pathway was uniquely enriched in multiple tissues (heart, kidney, lung, spleen) of gayal vs. cattle group. Among these, IL11RA is a member of the hematopoietic cytokine receptor family (Ng et al, 2021), which was uniquely up-regulated by 1.33 times in the heart of gayal. GP1BA is the alpha subunit of platelet surface membrane glycoprotein Ib (Luo et al, 2007), were 9.58, 3.90, 7.77, 11.41, 12.38, and 12.39-fold higher in the tissues (corresponding to heart, spleen, lung, kidney) of gayal than in the cattle, suggesting that the number of red blood cells and platelets might be increased.…”

Section: Expression Regulation Of Genes Involved In the Regulation Of Blood Cell Developmentmentioning

confidence: 99%

Comparative Transcriptome Analyses of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

Zhang

Wang

et al. 2022

Front. Genet.

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Gayal and yak are well adapted to the local high-altitude environments, yet the transcriptional regulation difference of the plateau environment among them remains obscure. Herein, cross-tissue and cross-species comparative transcriptome analysis were performed for the six hypoxia-sensitive tissues from gayal, yak, and cattle. Gene expression profiles for all single-copy orthologous genes showed tissue-specific expression patterns. By differential expression analysis, we identified 3020 and 1995 differentially expressed genes (DEGs) in at least one tissue of gayal vs. cattle and yak vs. cattle, respectively. Notably, we found that the adaptability of the gayal to the alpine canyon environment is highly similar to the yak living in the Qinghai-Tibet Plateau, such as promoting red blood cell development, angiogenesis, reducing blood coagulation, immune system activation, and energy metabolism shifts from fatty acid β-oxidation to glycolysis. By further analyzing the common and unique DEGs in the six tissues, we also found that numerous expression regulatory genes related to these functions are unique in the gayal and yak, which may play important roles in adapting to the corresponding high-altitude environment. Combined with WGCNA analysis, we found UQCRC1, COX5A are the shared differentially expression hub genes related to the energy supply of myocardial contraction in the heart-related modules of gayal and yak, and CAPS is a shared differentially hub gene among the hub genes of the lung-related module, which is related to pulmonary artery smooth muscle contraction. Additionally, EDN3 is the unique differentially expression hub gene related to the tracheal epithelium and pulmonary vasoconstriction in the lung of gayal. CHRM2 is a unique differentially expression hub gene that was identified in the heart of yak, which has an important role in the autonomous regulation of the heart. These results provide a basis for further understanding the complex transcriptome expression pattern and the regulatory mechanism of high-altitude domestication of gayal and yak.

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Section: Expression Regulation Of Genes Involved In the Regulation Of Blood Cell Developmentmentioning

confidence: 99%

Comparative Transcriptome Analyses of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

Zhang

Wang

et al. 2022

Front. Genet.

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“…Having established that IL11 is upregulated in TECs during AKI, we subjected Il11 null mice ( Il11 −/ − ) 29 or wild type controls to acute kidney injury and studied signaling effects, markers of pEMT as well as kidney morphology and function (Fig. 2a ).…”

Section: Resultsmentioning

confidence: 99%

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

et al. 2022

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The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.

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“…We suggest that therapeutic inhibition of IL11 might be considered for treating fibrotic diseases using a MOA that is differentiated from approved anti-fibrotic drugs. Given the safety data evident from humans and mice with IL11RA or IL11 loss of function and the lack of toxicities with long term anti-IL11 administration ( Widjaja et al, 2019 ; Ng et al, 2021 ), it is hoped that IL11-targeting approaches may have lesser side effects than current therapies.…”

Section: Discussionmentioning

confidence: 99%

Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts

Widjaja

Sivakumar

Dong

et al. 2021

Front. Mol. Biosci.

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In fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in Il11ra1 null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.

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

Cited by 28 publications

References 34 publications

Comparative Transcriptome Analyses of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

Comparative Transcriptome Analyses of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts

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