Leukemia Inhibitory Factor Receptor Research Articles

Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes.

Oncostatin M (OSM) is a unique Interleukin 6 (IL-6) family cytokine that plays pivotal roles in numerous biological events by signaling via two types of receptor complexes. While type I OSM receptor complex is formed by glycoprotein 130 (gp130) heterodimerization with Leukemia Inhibitory Factor receptor (LIFR), type II OSM receptor complex is composed of gp130 and OSM receptor (OSMR). OSM is an important contributor to multiple inflammatory diseases and cancers while OSM inhibition has been shown to be effective at reducing symptoms, making OSM an attractive therapeutic target. Using cryogenic electron microscopy (cryo-EM), we characterize full extracellular assemblies of human type I OSM receptor complex and mouse type II OSM receptor complex. The juxtamembrane domains of both complexes are situated in close proximity due to acute bends of the receptors. The rigid N-terminal extension of OSM contributes to gp130 binding and OSM signaling. Neither glycosylation nor pro-domain cleavage of OSM affects its activity. Mutagenesis identifies multiple OSM and OSMR residues crucial for complex formation and signaling. Our data reveal the structural basis for the assemblies of both type I and type II OSM receptor complexes and provide insights for modulation of OSM signaling in therapeutics.

Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the IL-6 cytokine family, such as Interleukin-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.

American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.

Association between circulating inflammatory proteins and benign prostatic disease: a Mendelian randomization study

Previous research has suggested that circulating inflammatory proteins are associated with benign prostatic disease (BPD). This Mendelian randomization (MR) study was conducted to further investigate the causal relationship between 91 inflammatory proteins and BPD. Genome-wide association study (GWAS) summarized data of benign prostatic hyperplasia (BPH) and prostatitis were obtained from the FinnGen Biobank. The latest study offered the GWAS data on 91 proteins related to inflammation. We performed a bidirectional MR to investigate the causal association between inflammatory proteins and BPD. The outcomes of the IVW method indicated that decreased levels of circulating interleukin-17 C (IL-17 C) (OR = 0.92, 95%CI = 0.85–0.99, p-value = 0.0344) were suggestively associated with a higher risk of BPH and elevated levels of interleukin-10 receptor subunit alpha (IL-10RA) (OR = 1.24, 95%CI = 1.05–1.47, p-value = 0.0132) and urokinase-type plasminogen activator (uPA) (OR = 1.13, 95%CI = 1.00–1.28, p-value = 0.0421) were suggestively related to a higher risk of prostatitis. Furthermore, reverse MR revealed that BPH may promote the expression of circulating factors, including natural killer cell receptor 2B4 (CD244) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), T-cell surface glycoprotein CD6 isoform (CD6) (OR = 1.07, 95%CI = 1.01–1.13, p-value = 0.0192), and leukemia inhibitory factor receptor (LIF-R) (OR = 1.07, 95%CI = 1.01–1.15, p-value = 0.0163). Moreover, the results of sensitivity analyses indicate that heterogeneity and horizontal pleiotropy are unlikely to distort the findings. The results of this study indicate a potential association between circulating inflammatory proteins and BPD, which may become new diagnostic indicators or drug targets for clinical application in the prevention and treatment of BPD. However, further investigation is required.

Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis.

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection.

AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.

Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.

Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.

Hsa_circ_0072309 Inhibits Oncogenesis in Hepatocellular Carcinoma by Epigenetic Activation of its Host Gene.

Recently, numerous studies have revealed the participation of circular RNAs (circRNAs) in cancer progression. Likewise, this research focused on circRNAs in hepatocellular carcinoma (HCC). A lowly expressed circRNA hsa_circ_0072309 in HCC was screened by analyzing the circRNA microarray GSE242797 and GSE216115 and identified in clinical specimens and cells. Subsequently, CCK-8, colony formation, and transwell assays were performed. The results revealed that hsa_circ_0072309 overexpression suppressed HCC cell proliferation, migration, invasion, and sorafenib resistance, whereas its suppression showed opposite results. Mechanistic investigation found an interaction between hsa_circ_0072309 and its host gene leukemia inhibitory factor receptor (LIFR) in HCC. We found that LIFR overexpression promoted the hsa_circ_0072309 formation. In turn, hsa_circ_0072309 recruited the E1A binding protein p300 to promote the enrichment of H3K27 acetylation (H3K27ac) in the LIFR enhancer, thus transcriptionally promoting LIFR expression. To conclude, we revealed a hsa_circ_0072309/LIFR regulatory loop in HCC, which may provide a potential target for HCC treatment.

Roles of leukemia inhibitory factor receptor in cancer.

Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.

Antagonist anti-LIF antibody derived from naive human scFv phage library inhibited tumor growth in mice

BackgroundLeukemia inhibitory factor (LIF) is a multifunctional member of the IL-6 cytokine family that activates downstream signaling pathways by binding to the heterodimer consisting of LIFR and gp130 on the cell surface. Previous research has shown that LIF is highly expressed in various tumor tissues (e.g. pancreatic cancer, breast cancer, prostate cancer, and colorectal cancer) and promotes cancer cell proliferation, migration, invasion, and differentiation. Moreover, the overexpression of LIF correlates with poor clinicopathological characteristics. Therefore, we hypothesized that LIF could be a promising target for the treatment of cancer. In this work, we developed the antagonist antibody 1G11 against LIF and investigated its anti-tumor mechanism and its therapeutic efficacy in mouse models.ResultsA series of single-chain variable fragments (scFvs) targeting LIF were screened from a naive human scFv phage library. These scFvs were reconstructed in complete IgG form and produced by the mammalian transient expression system. Among the antibodies, 1G11 exhibited the excellent binding activity to human, cynomolgus monkey and mouse LIF. Functional analysis demonstrated 1G11 could block LIF binding to LIFR and inhibit the intracellular STAT3 phosphorylation signal. Interestingly, 1G11 did not block LIF binding to gp130, another LIF receptor that is involved in forming the receptor complex together with LIFR. In vivo, intraperitoneal administration of 1G11 inhibited tumor growth in CT26 and MC38 models of colorectal cancer. IHC analysis demonstrated that p-STAT3 and Ki67 were decreased in tumor tissue, while c-caspase 3 was increased. Furthermore, 1G11 treatment improves CD3+, CD4 + and CD8 + T cell infiltration in tumor tissue.ConclusionsWe developed antagonist antibodies targeting LIF/LIFR signaling pathway from a naive human scFv phage library. Antagonist anti-LIF antibody exerts antitumor effects by specifically reducing p-STAT3. Further studies revealed that anti-LIF antibody 1G11 increased immune cell infiltration in tumor tissues.

LIFR regulates cholesterol-driven bidirectional hepatocyte-neutrophil cross-talk to promote liver regeneration.

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver.

Mendelian randomization of plasma lipidome, inflammatory proteome and heart failure.

Heart failure (HF) is a global health issue, with lipid metabolism and inflammation critically implicated in its progression. This study harnesses cutting-edge, expanded genetic information for lipid and inflammatory protein profiles, employing Mendelian randomization (MR) to uncover genetic risk factors for HF. We assessed genetic susceptibility to HF across 179 lipidomes and 91 inflammatory proteins using instrumental variables (IVs) from recent genome-wide association studies (GWASs) and proteome-wide quantitative trait loci (pQTL) studies. GWASs involving 47309 HF cases and 930014 controls were obtained from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium. Data on 179 lipids from 7174 individuals in a Finnish cohort and 91 inflammatory proteins from a European pQTL study involving 14824 individuals are available in the HGRI-EBI catalogue. A two-sample MR approach evaluated the associations, and a two-step mediation analysis explored the mediation role of inflammatory proteins in the lipid-HF pathway. Sensitivity analyses, including MR-RAPS (robust adjusted profile score) and MR-Egger, ensured result robustness. Genetic IVs for 162 lipids and 74 inflammatory proteins were successfully identified. MR analysis revealed a genetic association between HF and 31 lipids. Among them, 18 lipids, including sterol ester (27:1/18:0), cholesterol, 9 phosphatidylcholines, phosphatidylinositol (16:0_20:4) and 6 triacylglycerols, were identified as HF risk factors [odds ratio (OR)=1.037-1.368]. Cholesterol exhibited the most significant association with elevated HF risk [OR=1.368, 95% confidence interval (CI)=1.044-1.794, P=0.023]. In the inflammatory proteome, leukaemia inhibitory factor receptor (OR=0.841, 95% CI=0.789-0.897, P=1.08E-07), fibroblast growth factor 19 (OR=0.905, 95% CI=0.830-0.988, P=0.025) and urokinase-type plasminogen activator (OR=0.938, 95% CI=0.886-0.994, P=0.030) were causally negatively correlated with HF, whereas interleukin-20 receptor subunit alpha (OR=1.333, 95% CI=1.094-1.625, P=0.004) was causally positively correlated with HF. Mediation analysis revealed leukaemia inhibitory factor receptor (mediation proportion: 23.5%-25.2%) and urokinase-type plasminogen activator (mediation proportion: 9.5%-10.7%) as intermediaries in the lipid-inflammation-HF pathway. No evidence of directional horizontal pleiotropy was observed (P>0.05). This study identifies a genetic connection between certain lipids, particularly cholesterol, and HF, highlighting inflammatory proteins that influence HF risk and mediate this relationship, suggesting new therapeutic targets and insights into genetic drivers in HF.

Leukemia inhibitory factor receptor inhibition reduces stenosis grade in LDLR-/- mice

Leukemia inhibitory factor receptor inhibition reduces stenosis grade in LDLR-/- mice

The microenvironmental factors induced invasive tumor cells in glioblastoma

Glioblastoma (GBM) cells have the potential to switch from being “proliferative cells” to peritumoral “invasive cells”. Peritumoral GBM cells have highly invasive properties that allow them to survive surgery, leading to recurrence. The mechanisms underlying the manner in which the tumor microenvironment (TME) regulates the invasiveness of GBM remain unclear. Single-cell RNA sequencing analysis revealed heterogeneity in GBM cells, microglia and macrophages. In this study, the Oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) expression indicated higher invasiveness in core GBM cells. Under environmental stress, the expression of OSMR and LIFR were up-regulated with the effect of hypoxic, acidic, and low-glucose conditions in vitro. Functional experiments revealed that TME stress significantly influences the proliferation, migration and invasion of GBM cells. The differences in core/peripheral TMEs in GBM affected the invasive properties, indicating the significant role of OSMR expression within the TME in tumor progression and postoperative therapy.

Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification

Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.

Mutations in LIFR rewire the JAK/STAT signaling pathway: A study unveiling mechanistic details of Stüve-Wiedemann syndrome

Stüve-Wiedemann syndrome (SWS), a rare autosomal recessive disorder, characterized by diminutive size, curvature of the elongated bones, bent fingers, episodes of heightened body temperature, respiratory distress or periods of breath-holding, and challenges with feeding, especially causes fatality in infants. SWS is an outcome of potential missense mutations in the leukemia inhibitory factor receptor gene reflected as numerous amino acid mutations at protein level. Employing in silico tools and techniques like mutational screening with Pred_MutHTP, I-Mutant2.0, PANTHER.db, PolyPhen, to classify mutations as deleterious/destabilizing, in conjunction with experimental data analysis, P136A and S279P emerged as ‘effect’-causing mutations. Pre-existing knowledge suggests, SWS progression is effectuated conformationally altered and dysfunctional LIFR, unable to bind to LIF and further form the LIF/LIFR/gp130 signalling complex. To gain functional insights into the effect of the said mutations on the wild type protein, an all-atom, explicit, solvent molecular dynamics simulation was performed following docking approaches. Consequently, referring to the RMSD, RMSF, protein dynamic network analysis, energy landscape plots and domain motion analysis, it was revealed that unbound LIFR_WT was more prone to LIF binding as usual whereas the mutants exhibited considerable domain closure to inhibit LIF binding. We conducted binding affinity analysis via MM/GBSA and dissociation constant estimation after LIFR-LIF docking and found the WT_complex to be more stable and compact as a whole when compared to the flexible mutant complexes thus being associated with SWS. Our study offers a route for understanding molecular level implications upon LIFR mutations which opens an avenue for therapeutic interventions.

Genetically predicted inflammatory proteins and the risk of atrial fibrillation: a bidirectional Mendelian randomization study.

The causal associations between inflammatory factors and atrial fibrillation (AF) remained unclear. We aimed to investigate whether genetically predicted inflammatory proteins are related to the risk of AF, and vice versa. A bidirectional two-sample Mendelian randomization study was performed. The genetic variation of 91 inflammatory proteins were derived from genome-wide association study (GWAS) data of European ancestry (n = 14,824). Summary statistics for AF were obtained from a published meta-analysis study (n = 1,030,836) and the FinnGen study (n = 261,395). Genetically predicted fibroblast growth factor 5 (FGF5) was significantly positively associated with risk of AF [[odds ratio (OR): 1.07; 95% CI: 1.04-1.10; P < 0.01], and CD40l receptor was significantly negatively associated with risk of AF (OR: 0.95; 95% CI: 0.92-0.98; P = 0.02) in the meta-analysis study. In the FinnGen study, similar results were observed in FGF5 (OR: 1.11; 95% CI: 1.06-1.16; P < 0.01) and CD40l receptor (OR: 0.93; 95% CI: 0.89-0.97; P = 0.03) for AF. In the FinnGen study, TNF-beta was significantly positively associated with risk of AF (OR: 1.05; 95% CI: 1.02-1.09; P = 0.03) and leukemia inhibitory factor receptor was significantly negatively associated with risk of AF (OR: 0.86; 95% CI: 0.80-0.91; P = 0.001). The causal effect of AF on inflammatory proteins was not observed. Our study suggested that FGF5 and CD40l receptor have a potential causal association with AF, and targeting these factors may help in the treatment of AF.

Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS. Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS. Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk. Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.

Leukemia inhibitory factor receptor inhibition reduces stenosis grade and total serum cholesterol levels in a mouse model for atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Atherosclerosis is characterized by the accumulation of lipids and immune cells in the arterial wall and it is the main underlying pathology causing cardiovascular diseases (CVD). Cytokines are involved in all stages of atherosclerosis and most cytokines contribute to disease progression. For instance, IL-6 cytokine family members, such as IL-6, oncostatin-M and cardiotrophin-1, are closely related to CVDs. However, the role of leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, and its receptor (LIFR) in atherosclerosis remains unknown. Therefore, the aim of this study is to assess the contribution of LIFR signaling to atherosclerosis development by systemically inhibiting LIFR in an atherosclerotic mouse model. First, the expression of LIF and LIFR was examined using single-cell RNA sequencing data of human carotid artery plaques. Mast cells highly and exclusively express LIF, whereas LIFR was specifically expressed by activated endothelial cells. To validate LIFR signaling in vivo, female western-type diet fed Ldlr-/- mice were treated with LIFR inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. During the experiment, weights of the mice did not differ between groups, whereas total serum cholesterol levels were significantly reduced in EC359 treated mice (p=0.03). In particular, EC359 treatment reduced VLDL levels. Additionally, EC359 treatment significantly reduced Sr1, Abca1 and Lrp1 expression in the liver, suggesting an altered lipid metabolism in EC359 treated mice. Furthermore, LIFR inhibition affected innate immunity, both systemically and locally in the plaque. Neutrophil numbers were significantly increased in the circulation (ctrl 18.7±1.7%; EC359 28.0±2.0%; p=0.002) and aortic plaques (ctrl 3.9±0.8%; EC359 9.9±1.9%; p=0.003) of mice treated with EC359 compared to control mice. Moreover, LIFR inhibition affected circulating monocytes resulting in less inflammatory monocytes. The adaptive immune cells, such as T and B cells, remained largely unaffected. Collectively, the reduction of serum total cholesterol and increase in neutrophil numbers in EC359 treated mice resulted in a trend towards reduced atherosclerotic stenosis grade compared to control mice (39.8±1.4% versus 34.9±1.9%; p=0.054), but it did not affect plaque collagen and monocyte/macrophage content in the aortic root. Conclusively, LIFR signaling inhibition reduces atherosclerotic stenosis grade, lowers plasma total cholesterol levels and affects innate immunity.

The Role of Leukemia Inhibitory Factor in Cardiovascular Disease: Signaling in Inflammation, Coagulation, and Angiogenesis

Background: Cardiovascular disease (CVD) is one of the principal causes of mortality in the world. Various factors have been identified in the pathogenesis of CVD. Leukemia inhibitory factor (LIF) as a secretory cytokine is one of these factors. The LIF receptor is located on endothelial cells and plays a role in the expression of specific genes in these cells. Endothelial cells are the innermost cells of blood vessels, and defects in these cells cause endothelial dysfunction and eventually CVD. Methods: The present study is based on PubMed database information (1982–2022) using the following words: “cardiovascular disease,” “endothelial cells,” “leukemia inhibitory factor,” and “angiogenesis.” Results: LIF can cause arteriosclerotic plaques by activating inflammatory mechanisms in monocytes through the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. LIF can also induce vascular endothelial growth factor expression by activating signaling pathways, eventually leading to angiogenesis. Additionally, it can activate the coagulation cascade by factor VII production promotion within endothelial cells. Conclusion Understanding the interplay between LIF and the inflammation pathways, coagulation, and angiogenesis as key factors in CVD occurrence raises the possibility of targeting this factor as a potential strategy to mitigate CVD risk.