Programmed microalgae-gel promotes chronic wound healing in diabetes.

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/cm2), green HEA (GHEA) with efficient photothermal conversion mediate wound surface disinfection. By decreasing the light intensity (658 nm, 0.1 W/cm2), 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.

Piezoelectricity, Pyroelectricity, and Ferroelectricity in Biomaterials and Biomedical Applications.

Piezoelectric, pyroelectric, and ferroelectric materials are considered unique biomedical materials due to their dielectric crystals and asymmetric centers that allow them to directly convert various primary forms of energy in the environment, such as sunlight, mechanical energy, and thermal energy, into secondary energy, such as electricity and chemical energy. These materials possess exceptional energy conversion ability and excellent catalytic properties, which have led to their widespread usage within biomedical fields. Numerous biomedical applications have demonstrated great potential with these materials, including disease treatment, biosensors, and tissue engineering. For example, piezoelectric materials are used to stimulate cell growth in bone regeneration, while pyroelectric materials are applied in skin cancer detection and imaging. Ferroelectric materials have even found use in neural implants that record and stimulate electrical activity in the brain. This paper reviews the relationship between ferroelectric, piezoelectric, and pyroelectric effects and the fundamental principles of different catalytic reactions. It also highlights the preparation methods of these three materials and the significant progress made in their biomedical applications. The review concludes by presenting key challenges and future prospects for efficient catalysts based on piezoelectric, pyroelectric, and ferroelectric nanomaterials for biomedical applications.

Pyrolysis temperature matters: Biochar-derived dissolved organic matter modulates aging behavior and biotoxicity of microplastics.

Microplastics (MPs) have emerged as a novel and highly concerning contaminant that is ubiquitous in the aqueous environment. However, the aging of MPs induced by dissolved organic matter (DOM), especially biochar-derived dissolved organic matter (BDOM), and the biological toxicity after aging are not fully understood. In this study, the effects of biochar-derived BDOMs on the photoaging and biotoxicity of MPs were investigated at different pyrolysis temperatures using micro-scale polyethylene (PE) as an example. The results showed that the amount of ·OH generated by the BDOM/PE systems was related to the molecular composition and structure of BDOMs. High temperature BDOM7/9 with less lignin-like (34.33 % / 41.80 %) and more lipid (24.58 % / 19.88 %) content could produce more ·OH by itself, and its binding ability with PE was weaker due to its less hydrophobic components (SUVA260 = 0.10 / 0.11), which resulted in a weaker shading effect and less inhibition of the system, thus resulting in more ·OH production in the high temperature BDOM7/9/PE system. However, the involvement of BDOM, although favoring the long-term stable ·OH production of the system, did not significantly promote the photoaging of MPs. Furthermore, combined in vivo and in vitro biotoxicity studies of MPs showed that photoaging PE with the involvement of BDOM greatly improved systemic inflammation and tissue damage, as well as reactive oxygen species (ROS, such as ·OH and -OH)-induced cell death. For example, the addition of BDOM5/PE-light reduced the cell death of human lung, liver, and kidney cells from 54.70 %, 69.39 %, and 48.35 % to 22.78 %, 33.13 %, and 25.83 %, respectively, compared to the PE-light group. The results of this study contribute to an in-depth understanding of the environmental behavior of BDOM and MPs systems.

Self-triggered thermoelectric nanoheterojunction for cancer catalytic and immunotherapy.

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 (Bi0.5Sb1.5Te3/CaO2 nanosheets, BST/CaO2 NSs) with self-built-in electric field facilitated charge separation is fabricated. Upon exposure to TME, the CaO2 coating undergoes rapid hydrolysis, releasing Ca2+, H2O2, and heat. The resulting temperature difference on the BST NSs initiates a thermoelectric effect, driving reactive oxygen species production. H2O2 not only serves as a substrate supplement for ROS generation but also dysregulates Ca2+ channels, preventing Ca2+ efflux. This further exacerbates calcium overload-mediated therapy. Additionally, Ca2+ promotes DC maturation and tumor antigen presentation, facilitating immunotherapy. It is worth noting that the CaO2 NP coating hydrolyzes very slowly in normal cells, releasing Ca2+ and O2 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.

Genetically Engineered-Cell-Membrane Nanovesicles for Cancer Immunotherapy.

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.

Electrons of d-orbital (Mn) and p-orbital (N) enhance the photocatalytic degradation of antibiotics by biochar while maintaining biocompatibility: A combined chemical and biological analysis.

Photocatalytic oxidation technology holds promise for ideal advanced treatment of antibiotic wastewater. Single-atom catalysts (SACs) are a new hotspot in catalytic science, but the photochemical studies on the removal of antibiotics from water and biocompatibility after entering the environment are scarce. In this work, we prepared a single Mn atom immobilized on N-doped biochar (Mn@N-Biochar) by impregnation calcination method for enhancing photocatalytic degradation of sulfanilamide (SNM) in different types of various water systems. Compared with the original biochar, Mn@N-Biochar showed enhanced SNM degradation and TOC removal capacity. DFT calculation concluded that the electrons of d-orbital (Mn) and p-orbital (N) altered the electronic structure of biochar and enhanced the photoelectric performance. It was shown that Mn@N-Biochar caused negligible systemic inflammation and tissue damage when given orally in mice, and also did not alter cell death and ROS production in human lung, kidney, and liver cells, as compared with biochar. We are convinced that Mn@N-Biochar could enhance the photocatalytic degradation of antibiotics while maintaining biocompatibility, which could be a promising strategy for wastewater treatment.

[Research progress of transcription activating factor 3 in regulating the alveolar macrophages in acute respiratory distress syndrome].

Acute respiratory distress syndrome (ARDS) refers to acute diffuse lung injury caused by a variety of intrapulmonary and/or extrapulmonary factors such as infection and trauma. Uncontrolled inflammatory response is the main pathological feature. Different functional states of alveolar macrophages have different effects on inflammatory response. Transcription activating factor 3 (ATF3) is a fast response gene in the early stage of stress. In recent years, it has been found that ATF3 plays an important role in regulating the inflammatory response of ARDS by regulating the function of macrophages. This paper reviews the regulatory effects of ATF3 on alveolar macrophage polarization, autophagy and endoplasmic reticulum stress and its effects on the inflammatory process of ARDS, aiming to provide a new research direction for the prevention and treatment of ARDS.

Nanoheterojunction-Mediated Thermoelectric Strategy for Cancer Surgical Adjuvant Treatment and ß-Elemene Combination Therapy.

As an indispensable strategy for tumor treatment, surgery may cause two major challenges: tumor recurrence and wound infection. Here, a thermoelectric therapeutic strategy is provided as either an independent cancer therapy or surgical adjuvant treatment. Bi0.5 Sb1.5 Te3 (BST) and Bi2 Te2.8 Se0.2 (BTS) nanoplates composed of Z-scheme thermoelectric heterojunction (BST/BTS) are fabricated via a two-step hydrothermal processes. The contact between BST and BTS constructs an interfacial electric field due to Fermi energy level rearrangement, guiding electrons in the conductive band (CB) of BTS combine with the holes in the valance band (VB) of BST, leaving stronger reduction/oxidation potentials of electrons and holes in the CB of BST and the VB of BTS. Moreover, under a mild temperature gradient, another self-built-in electric field is formed facilitating the migration of electrons and holes to their surfaces. Based on the PEGylated BST/BTS heterojunction, a novel thermoelectric therapy platform is developed through intravenous injection of BST/BTS and external cooling of the tumors. This thermoelectric strategy is also proved effective for combination cancer therapy with ß-elemene. Moreover, the combination of heterojunction and hydrogel is administrated on the wound after surgery, achieving efficient residual tumor treatment and antibacterial effects.

The marriage of Xenes and hydrogels: Fundamentals, applications, and outlook.

Hydrogels have blossomed as superstars in various fields, owing to their prospective applications in tissue engineering, soft electronics and sensors, flexible energy storage, and biomedicines. Two-dimensional (2D) nanomaterials, especially 2D mono-elemental nanosheets (Xenes) exhibit high aspect ratio morphology, good biocompatibility, metallic conductivity, and tunable electrochemical properties. These fascinating characteristics endow numerous tunable application-specific properties for the construction of Xene-based hydrogels. Hierarchical multifunctional hydrogels can be prepared according to the application requirements and can be effectively tuned by different stimulation to complete specific tasks in a spatiotemporal sequence. In this review, the synthesis mechanism, properties, and emerging applications of Xene hydrogels are summarized, followed by a discussion on expanding the performance and application range of both hydrogels and Xenes.

Novel biodegradable two-dimensional vanadene augmented photoelectro-fenton process for cancer catalytic therapy.

Fenton reaction-based chemodynamic therapy is hardly a self-sufficient cancer treatment, due to its stringent reaction conditions, limited substrate concentration, and negative feedback from the tumor microenvironment. Herein, we synthesized a novel two-dimensional (2D) vanadium-based nanosheets (Vanadene, V NSs) with polyvalent surfaces (VIV/VV), a very narrow band gap of 0.8 eV, and high biodegradability by a liquid-phase exfoliation strategy. The polyvalent surface endowed its multiple capabilities to modulate TME through GSH consumption and O2 production via VV and to catalyze a Fenton-like reaction to produce ·OH under a mild condition via VIV. In addition, efficient energy conversions including near-infrared (NIR)-thermal conversion (photothermal therapy, PTT) and NIR-electron conversion (photodynamic therapy, PDT) were ensured by the narrow band gap, in which NIR-thermal conversion enhanced the Fenton-like reaction activity through accelerating ionization while NIR-electron conversion catalyzed the conversion of O2 to ·O2- for further breaking redox homeostasis. Moreover, V NSs-based nanocatalyst can be slowly degraded into non-toxic species, enabling it to be innocuously eliminated from the body after completing tumor eradication by single drug injection and single NIR irradiation. Therefore, this study provides new insights into a universal nanoplatform for NIR-enhanced combination cancer therapy, highlighting the utility of 2D V NSs in the field of biomedicine.

Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury.

N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1ß, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.

Inhibition of IL11 Signaling Reduces Aortic Pathology in Murine Marfan Syndrome.

BACKGROUND: Marfan syndrome (MFS) is associated with TGF (transforming growth factor) ß-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFß 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 Fbn1C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11EGFP/+) 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 Il11EGFP/+ 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.

[Research progress on release mechanism of high mobility group protein B1 in acute respiratory distress syndrome].

High mobility group protein B1 (HMGB1), a highly conversed non-histone nucleoproteins with strong pro-inflammatory property, is one of the inflammatory mediator of the acute respiratory distress syndrome (ARDS). Numerous studies have confirmed that HMGB1 regulates ARDS by binding to receptor for advanced glycation end product (RAGE), Toll-like receptor (TLR) and etc. And it can significantly increase the mortality of ARDS. But the mechanism of HMGB1 release is still unclear. This study focuses on the HMGB1 release progress, which connected with Janus kinases/signal transducer and activator of transcription (JAK/STAT), nuclear factor-κB (NF-κB), Notch, inflammasome, tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS), peroxisome proliferator-activated receptor (PPAR) and other signaling or dependent pathways in ARDS.

The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling.

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 Il11 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.

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

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 TGFß1. 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.

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

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.

Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH.

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.

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models.

Transforming growth factor beta-1 (TGFß1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFß1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFß1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFß1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease.

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.

Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis.

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 (IL11) 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 (Il11ra1)-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.