Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

Effenberger, M.; Grabherr, F.; Schaefer, B.; Grander, C.; Mayr, L.; Schwaerzler, J.; Enrich, B.; Moser, P.; Fink, J.; Pedrini, A.; Jaschke, N.; Freund, M.; Loizides, A.; Bale, R.; Putzer, D.; Widjaja, A. A.; Schaefer, S.; Cook, S.; Zoller, H.; Oberhuber, G.; Adolph, T. E.; Tilg, H.

doi:10.1101/2021.08.24.456749

Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.08.24.456749

Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

View original source ↗Export metadata ↓

Abstract

BackgroundAlcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide with limited treatment options. Interleukin-11 (IL-11) is a pro-fibrotic, pro-inflammatory cytokine with increasingly recognized toxicities in parenchymal and epithelial cells. AimThe aim of this study was to explore the prognostic value of IL-11 serum levels in patients suffering from AH and cirrhosis of various etiology and to understand the role of IL-11 in experimental ALD. MethodsIL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort including 186 patients. Ethanol-fed wildtype mice were treated with a neutralizing murine IL-11 receptor-antibody (anit-IL11RA) and thereafter examined for severity signs and markers of ALD. ResultsHuman IL-11 serum concentration and liver tissue expression increased with severity of liver disease and were most pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 picograms/milliliter was a MELD independent risk factor for transplant-free liver disease survival in patients with compensated and decompensated cirrhosis. Findings were confirmed in an independent cohort. In mice, severity of alcohol-induced liver inflammation was positively correlated to enhanced hepatic IL-11 expression. Pretreatment with a neutralizing anti-IL11RA inhibited hepatic inflammation and mice were protected from ethanol-induced liver injury. In comparison to IgG-control, ethanol-fed mice treated with anti-IL11RA showed decreased steatosis, hepatic neutrophil infiltration, and expression of pro-inflammatory cytokines. ConclusionIL-11 plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signaling might be a therapeutic option in human ALD, particularly AH.

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Effenberger, M., Grabherr, F., Schaefer, B., Grander, C., Mayr, L., Schwaerzler, J., Enrich, B., Moser, P., Fink, J., Pedrini, A., Jaschke, N., Freund, M., Loizides, A., Bale, R., Putzer, D., Widjaja, A. A., Schaefer, S., Cook, S., Zoller, H., Oberhuber, G., Adolph, T. E., Tilg, H.. 2021-08-25. Interleukin-11 plays a key role in human and mouse alcohol-related liver disease. https://doi.org/10.1101/2021.08.24.456749

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

De novo design of CR2 binder as vaccine scaffold

Efficient B cell activation during vaccine-induced humoral immunity relies on both B cell receptor (BCR) antigen recognition and synergistic signaling from co-receptors. Complement receptor 2 (CR2), the primary BCR co-receptor on B cells, lowers the activation threshold and amplifies downstream kinase signaling by orders of magnitude when engaged by complement fragment C3d decorated antigens. Targeting CR2 therefore represents a rational vaccine enhancement strategy, yet native C3d suffers from low affinity, poor stability, and manufacturing challenges. Here, we report the de novo design of a highly stable, high-affinity CR2 binder using deep learning driving protein design methods. Biophysical characterization, high-resolution cryoEM structural determination, and functional assays in vitro and in vivo confirm that the designed binder matches computational design models and specifically engages CR2 to boost B cell activation. When fused to antigen as a vaccine scaffold, the trimeric CR2 binder elicits robust humoral immune responses comparable to nanoparticle vaccines, while retaining the simplicity of single-chain protein production. Our work establishes a modular CR2 targeting vaccine scaffold platform with broad translational potential for next-generation protein vaccines.

immunology↗

bioRxiv2026

Chronic opioid-associated immune dysregulation among people living with HIV

Objectives: Persistent immune dysregulation contributes to chronic disease among people living with HIV (PWH), even after viral suppression with antiretroviral therapy (ART). Although chronic opioid exposure is associated with adverse clinical outcomes, its impact on immune homeostasis during ART remains incompletely understood. We investigated whether opioid use disorder (OUD) is associated with persistent systemic and cellular immune dysregulation despite ART-mediated reductions in HIV viral load (VL). Methods: Peripheral blood was collected longitudinally from PWH with OUD (PWH/OUD+) and detectable HIV VL during 6 months of optimized ART (months 0, 3, and 6). A reference cohort of PWH without OUD (PWH/OUD-) and suppressed HIV VL provided a single blood sample. Immune profiling included plasma inflammatory biomarkers, multiplex cytokine analyses, spectral flow cytometry, and assessment of monocyte cytokine responses following lipopolysaccharide (LPS) stimulation. Mixed-effects models adjusted for HIV VL and VL-stratified analyses were performed. Results: PWH/OUD+ exhibited persistent immune dysregulation despite reductions in HIV VL. Plasma sCD163, sCD14, fractalkine, and I-TAC remained elevated, whereas TGF-{beta}1 was reduced. OUD was associated with expansion of CD16 monocytes and altered expression of CCR2, CD38, and CD11b. CD4 and CD8 T cells, NK cells, and B cells also exhibited persistent alterations in markers of activation, metabolism, and trafficking. Monocytes from PWH/OUD+ displayed attenuated cytokine responses following LPS stimulation. Conclusions: OUD is associated with persistent systemic and cellular immune dysfunction in PWH despite ART-mediated viral suppression, supporting opioid exposure as an independent contributor to chronic immune dysregulation that may promote inflammation, immune dysfunction, and long-term HIV-associated comorbidities. Keywords: HIV, Opioid-use disorder, innate immunity, cytokine

immunology↗

bioRxiv2026

The mitochondrial RNA extrusion-induced innate immunity is regulated by N6-methyladenosine machinery

Mitochondrial RNA (mtRNA) released into the cytosol functions as a damage associated molecular pattern that activates pattern-recognition receptor (PRR)-mediated inflammation, yet its release mechanisms and cytoplasmic fate remain poorly understood. Here we report that chemical Abt-373-treatment and Vesicular stomatitis virus (VSV) infection induce mtRNA extrusion through Bax/Bak and VDAC1 channels, accompanied by mtDNA release. Extruded mtRNA in A549 cells activates multiple cytosolic PRRs, including RIG-I, MDA5, TLR3/7/8, and PKR, each contributing differentially to the innate immune signaling. Analysis of GEO datasets and methylated RNA immunoprecipitation (MeRIP) assays further reveals that mtRNA carries methyladenosine (m6A) modification. m6A machinery proteins are involved in the cytoplasmic retention time of mtRNA and its interaction with RIG-I, thereby modulating mtRNA-induced innate immunity. Thus, our work establishes in vitro models of mtRNA extrusion, and highlights m6A-dependent modulation as a potential therapeutic target for mtRNA-driven inflammation.

immunology↗