IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. ...Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.
We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH.
We ...stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1–/–) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays.
HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1–/– mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1–/– mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1.
Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.
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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here, we show that interleukin-11 (
) ...is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2
), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner. In mice, fibroblast-specific transgenic expression or administration of murine IL-11 induces lung myofibroblasts and causes lung fibrosis. IL-11 receptor subunit alpha-1 (
)-deleted mice, whose lung fibroblasts are unresponsive to profibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11-neutralizing antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice. These data prioritize IL-11 as a drug target for lung fibrosis and IPF.
Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been ...characterized. We generated IL11 knockout (Il11
) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11
mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11
mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11
female mice are infertile. Unlike Il11ra1
mice, Il11
mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.
Abstract
The exogenous excitation requirement and electron-hole recombination are the key elements limiting the application of catalytic therapies. Here a tumor microenvironment (TME)-specific ...self-triggered thermoelectric nanoheterojunction (Bi
0.5
Sb
1.5
Te
3
/CaO
2
nanosheets, BST/CaO
2
NSs) with self-built-in electric field facilitated charge separation is fabricated. Upon exposure to TME, the CaO
2
coating undergoes rapid hydrolysis, releasing Ca
2+
, H
2
O
2
, and heat. The resulting temperature difference on the BST NSs initiates a thermoelectric effect, driving reactive oxygen species production. H
2
O
2
not only serves as a substrate supplement for ROS generation but also dysregulates Ca
2+
channels, preventing Ca
2+
efflux. This further exacerbates calcium overload-mediated therapy. Additionally, Ca
2+
promotes DC maturation and tumor antigen presentation, facilitating immunotherapy. It is worth noting that the CaO
2
NP coating hydrolyzes very slowly in normal cells, releasing Ca
2+
and O
2
without causing any adverse effects. Tumor-specific self-triggered thermoelectric nanoheterojunction combined catalytic therapy, ion interference therapy, and immunotherapy exhibit excellent antitumor performance in female mice.
Chronic diabetic wounds are at lifelong risk of developing diabetic foot ulcers owing to severe hypoxia, excessive reactive oxygen species (ROS), a complex inflammatory microenvironment, and the ...potential for bacterial infection. Here we develop a programmed treatment strategy employing live Haematococcus (HEA). By modulating light intensity, HEA can be programmed to perform a variety of functions, such as antibacterial activity, oxygen supply, ROS scavenging, and immune regulation, suggesting its potential for use in programmed therapy. Under high light intensity (658 nm, 0.5 W/cm
), green HEA (GHEA) with efficient photothermal conversion mediate wound surface disinfection. By decreasing the light intensity (658 nm, 0.1 W/cm
), the photosynthetic system of GHEA can continuously produce oxygen, effectively resolving the problems of hypoxia and promoting vascular regeneration. Continuous light irradiation induces astaxanthin (AST) accumulation in HEA cells, resulting in a gradual transformation from a green to red hue (RHEA). RHEA effectively scavenges excess ROS, enhances the expression of intracellular antioxidant enzymes, and directs polarization to M2 macrophages by secreting AST vesicles via exosomes. The living HEA hydrogel can sterilize and enhance cell proliferation and migration and promote neoangiogenesis, which could improve infected diabetic wound healing in female mice.
Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global posttranscriptional mechanisms underlying fibroblast-to-myofibroblast ...conversion in the heart have not been explored.
Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these posttranscriptional mechanisms are also active in the diseased fibrotic human heart.
We generated nucleotide-resolution translatome data during the transforming growth factor β1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation, and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in posttranscriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same posttranscriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as Pumilio RNA binding family member 2 (PUM2) and Quaking (QKI) that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward profibrotic myofibroblasts in response to transforming growth factor β1.
We reveal widespread translational effects of transforming growth factor β1 and define novel posttranscriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease, and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.
It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) ...promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for
exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.
Repetitive pulmonary injury causes fibrosis and inflammation that underlies chronic lung diseases such as idiopathic pulmonary fibrosis (IPF). Interleukin 11 (IL11) is important for pulmonary ...fibroblast activation but the contribution of fibroblast‐specific IL11 activity to lung fibro‐inflammation is not known. To address this gap in knowledge, we generated mice with loxP‐flanked Il11ra1 and deleted the IL11 receptor in adult fibroblasts (CKO mice). In the bleomycin (BLM) model of lung fibrosis, CKO mice had reduced fibrosis, lesser fibroblast ERK activation, and diminished immune cell STAT3 phosphorylation. Following BLM injury, acute inflammation in CKO mice was similar to controls but chronic immune infiltrates and pro‐inflammatory gene activation, including NF‐kB phosphorylation, were notably reduced. Therapeutic prevention of IL11 activity with neutralizing antibodies mirrored the effects of genetic deletion of Il11ra1 in fibroblasts. These data reveal a new function for IL11 in pro‐inflammatory lung fibroblasts and highlight the important contribution of the stroma to inflammation in pulmonary disease.
The advent of immunotherapy has marked a new era in cancer treatment, offering significant clinical benefits. Cell membrane as drug delivery materials has played a crucial role in enhancing cancer ...therapy because of their inherent biocompatibility and negligible immunogenicity. Different cell membranes are prepared into cell membrane nanovesicles (CMNs), but CMNs have limitations such as inefficient targeting ability, low efficacy, and unpredictable side effects. Genetic engineering has deepened the critical role of CMNs in cancer immunotherapy, enabling genetically engineered-CMN (GCMN)-based therapeutics. To date, CMNs that are surface modified by various functional proteins have been developed through genetic engineering. Herein, a brief overview of surface engineering strategies for CMNs and the features of various membrane sources is discussed, followed by a description of GCMN preparation methods. The application of GCMNs in cancer immunotherapy directed at different immune targets is addressed as are the challenges and prospects of GCMNs in clinical translation.