Inhaled siRNA nanoparticles targeting
            <i>IL11</i>
            inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge

Bai, Xin; Zhao, Guolin; Chen, Qijing; Li, Zhongyu; Gao, Mingyang; Ho, William W.; Xu, Xiaoyang; Zhang, Xue‐Qing

doi:10.1126/sciadv.abn7162

Cited by 68 publications

(39 citation statements)

References 57 publications

(59 reference statements)

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“…Tissue images indicated that there was no AA3-DLin LNP induced inflammation detected after comparison with PBS control groups (Figure S8 and S9). − …”

Section: Resultsmentioning

confidence: 99%

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

Zhang

et al. 2022

ACS Nano

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Ionizable cationic lipid-containing lipid nanoparticles (LNPs) are the most clinically advanced non-viral gene delivery platforms, holding great potential for gene therapeutics. This is exemplified by the two COVID-19 vaccines employing mRNA-LNP technology from Pfizer/BioNTech and Moderna. Herein, we develop a chemical library of ionizable cationic lipids through a one-step chemical-biological enzyme-catalyzed esterification method, and the synthesized ionizable lipids were further prepared to be LNPs for mRNA delivery. Through orthogonal design of experiment methodology screening, the top-performing AA3-DLin LNPs show outstanding mRNA delivery efficacy and long-term storage capability. Furthermore, the AA3-DLin LNP COVID-19 vaccines encapsulating SARS-CoV-2 spike mRNAs successfully induced strong immunogenicity in a BALB/c mouse model demonstrated by the antibody titers, virus challenge, and T cell immune response studies. The developed AA3-DLin LNPs are an excellent mRNA delivery platform, and this study provides an overall perspective of the ionizable cationic lipids, from aspects of lipid design, synthesis, screening, optimization, fabrication, characterization, and application.

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“…Tissue images indicated that there was no AA3-DLin LNP induced inflammation detected after comparison with PBS control groups (Figure S8 and S9). − …”

Section: Resultsmentioning

confidence: 99%

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

Zhang

et al. 2022

ACS Nano

Self Cite

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“…However, many of the original insights into IL11 biology were based on the use of rhIL11 in the mouse, which has unexpected effects [ 7 , 8 ]. This realization underpins the discovery that IL11 is profibrotic [ 4 , 5 , 6 , 9 , 11 ], whereas the earlier literature had reported it as anti-fibrotic [ 3 , 40 , 41 , 42 ]. We suggest that, as it was for fibrosis, the role for IL11 in inflammation has been misinterpreted.…”

Section: Discussionmentioning

confidence: 99%

“…However, species-matched IL11 was recently found to have ERK-dependent pro-fibrotic activity in fibroblasts [ 4 , 5 , 6 , 7 ], and it transpires that rhIL11 has unexpected activity in the mouse and paradoxically inhibits endogenous murine IL11 [ 8 ]. In mammals, IL11 is now largely accepted to be pro-fibrotic [ 9 ] and is increasingly viewed as anti-regenerative [ 8 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues

Widjaja

Chothani

Sivakumar

et al. 2022

IJMS

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Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10−5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.

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“…However, many of the original insights into IL11 biology were based on the use of rhIL11 in the mouse, which has unexpected effects [7,8]. This discovery underpins the realization that IL11 is profibrotic [4–6,9,11] whereas the earlier literature had reported it as anti-fibrotic [3,39–41]. We suggest that, as it was for fibrosis, the role for IL11 in inflammation is misinterpreted.…”

Section: Discussionmentioning

confidence: 96%

“…However, species matched IL11 was recently found to have ERK-dependent pro-fibrotic activity in fibroblasts [4][5][6][7] and it transpires that rhIL11 has unexpected activity in the mouse and inhibits endogenous murine IL11 [8]. In mammals, IL11 is now largely accepted to be pro-fibrotic [9] and is increasingly viewed as anti-regenerative [8,10,11].…”

Section: Introductionmentioning

confidence: 99%

IL11 stimulates IL33 expression and proinflammatory fibroblast activation

Widjaja

Chothani

Sivakumar

et al. 2022

Preprint

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Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8x10-5) and IL1RL1, its cognate receptor, was similarly increased (18-fold, P=1.1x10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts.

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Inhaled siRNA nanoparticles targeting IL11 inhibit lung fibrosis and improve pulmonary function post-bleomycin challenge

Cited by 68 publications

References 57 publications

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

Enzyme-Catalyzed One-Step Synthesis of Ionizable Cationic Lipids for Lipid Nanoparticle-Based mRNA COVID-19 Vaccines

IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues

IL11 stimulates IL33 expression and proinflammatory fibroblast activation

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