An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate anti-viral immune response DOI Creative Commons
Bojan Polić, Marko Šestan, Ante Benić

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 5, 2024

Abstract Viral infection makes us feel sick. The extent of these changes to our metabolism are relative the severity disease. Whether blood glucose levels subject infection-induced modulation is largely unknown. Here we show that strong, non-lethal restricts systemic availability which promotes antiviral IFN-I response. Following viral mice, find IFNγ produced by γδ T cells directly stimulates pancreatic β-cells increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens endogenous output liver. Glucose restriction enhances type-I interferon production curtailing lactate-mediated inhibition IRF3 and NF-κB signaling. Induced hyperglycemia constrained increased mortality upon infection. Our findings identify as a physiological mechanism bring body into heightened state responsiveness pathogens. This immune-endocrine circuit disrupted in hyperglycemia, explains why people with metabolic disease more susceptible

Language: Английский

Molecular mechanisms in MASLD/MASH-related HCC DOI
Xiaobo Wang, Liang Zhang, Bingning Dong

et al.

Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

Liver cancer is the third leading cause of cancer-related deaths and ranks as sixth most prevalent type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, its more severe manifestation, NASH steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% population. The increased prevalence disease MASH parallel to increasing rates obesity-associated diseases, including 2 diabetes, insulin resistance, fatty diseases. can progress MASH-related HCC (MASH-HCC) in about 2% cases each year, influenced by various factors such genetic mutations, carcinogen exposure, immune microenvironment, microbiome. MASH-HCC exhibits distinct molecular characteristics compared other causes affects both men women equally. management early intermediate-stage typically involves surgery locoregional therapies, while advanced treated with systemic anti-angiogenic therapies checkpoint inhibitors. In this comprehensive review, we consolidate previous research findings also providing current insights into intricate processes underlying development. We delve MASH-HCC-associated variations somatic progression models, multiomics analysis, immunological microenvironmental impacts, discuss targeted/combined overcome evasion biomarkers recognize treatment responders. By furthering our comprehension mechanisms MASH-HCC, goal catalyze advancement potent strategies, ultimately enhanced patient outcomes.

Language: Английский

Citations

41
The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis DOI Open Access
Karlo Mladenić, Maja Lenartić, Sonja Marinović

et al.

European Journal of Immunology, Journal Year: 2024, Volume and Issue: 54(4)

Published: Feb. 5, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter the global adult population. A key event in pathophysiology MASLD development metabolic-associated steatohepatitis (MASH), which greatly increases chances developing cirrhosis and hepatocellular carcinoma. The underlying cause MASH multifactorial, but accumulating evidence indicates that inflammatory process hepatic microenvironment typically follows pattern can be roughly divided into three stages: (1) Detection hepatocyte stress by tissue-resident immune cells including γδ T CD4

Language: Английский

Citations

18
MAFLD as part of systemic metabolic dysregulation DOI
Jing Zhao, Lu Liu,

Yingying Cao

et al.

Hepatology International, Journal Year: 2024, Volume and Issue: 18(S2), P. 834 - 847

Published: April 9, 2024

Language: Английский

Citations

15
An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response DOI
Marko Šestan, Sanja Mikašinović, Ante Benić

et al.

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(6), P. 981 - 993

Published: May 29, 2024

Language: Английский

Citations

7
Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death DOI Creative Commons
R Lambrecht, M. Eugenia Delgado,

Vincent Gloe

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113513 - 113513

Published: Nov. 30, 2023

The nuclear receptor liver homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen alpha elevated κB (NF-κB) activity, while overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction LRH-1's ligand-binding domain the Rel homology subunit RelA. Mechanistically, increased transcription anti-apoptotic target genes proteasomal degradation pro-apoptotic BCL-2 interacting mediator prevent mitochondrial ultimately protect TNF-induced damage. Collectively, our study emphasizes as a critical, sex-dependent regulator healthy diseased liver.

Language: Английский

Citations

12
The immunology of sickness metabolism DOI Creative Commons
Felix M. Wensveen, Marko Šestan, Bojan Polić

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(9), P. 1051 - 1065

Published: Aug. 6, 2024

Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are part of carefully regulated process depends on tissue-specific interactions between the immune system and organs involved regulation systemic homeostasis. Immune-mediated homeostatic parameters lead to altered production uptake nutrients circulation, which modifies metabolic rate key organs. This is what experience being The purpose sickness generate environment body optimally able fight while denying vital for replication pathogens. Sickness cells, mediate responses tailored nature magnitude threat. As increases severity, so do number type cells level affected, dictates degree Interestingly, many alterations associated with disease appear overlap immune-mediated observed following infection. Targeting processes involving activated therefore holds great potential treating both people severe those disease. In this review, will discuss how communicates situ homeostasis communication impacted by

Language: Английский

Citations

4
Efficacy of measuring natural killer-activating receptor ligands to predict the pathogenesis of metabolic dysfunction-associated steatotic liver disease DOI
Jun Arai, Akinori Okumura,

Satoshi Kimoto

et al.

Hepatology International, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

Language: Английский

Citations

0
Immune cells in metabolic associated fatty liver disease: Global trends and hotspots (2004-2024) DOI
Wenying Qi,

Shihao Zheng,

Size Li

et al.

World Journal of Hepatology, Journal Year: 2025, Volume and Issue: 17(3)

Published: March 25, 2025

The interplay between immune cells and metabolic associated fatty liver disease (MAFLD) is a critical research frontier, bridging immunology hepatology. bibliometric findings can guide future funding priorities in the field by highlighting key areas of focus potential therapeutic targets. To analyze literature on MAFLD, identifying trends hotspots. A systematic search Web Science Core Collection from January 1, 2004 to May 20, 2024, yielded 1936 articles MAFLD. Excluding non-research documents, data were analyzed using R packages Cluster profiler, enrichplot, ggplot2, VOSviewer CiteSpace. Visualizations created for countries, institutions, authors, journals, fields, co-cited references, keywords, genes, diseases, with gene Citexs. gained momentum 2006, United States America China as leading contributors. Key themes included oxidative stress, syndrome, fibrosis, role Kupffer cells. Bioinformatics identified interleukin-6, tumor necrosis factor signal transducer activator transcription 3 central proteins responses inflammation, suggesting targets Clinically, these hub genes play pivotal roles pathogenesis For instance, targeting signaling pathway could reduce while modulating interleukin-6 expression may improve function, offering new strategies MAFLD therapy. This analysis reports hotspots emerging through bioinformatics.

Language: Английский

Citations

0
Inflammation in MASLD Progression and Cancer DOI Creative Commons
Yeon Soo Kim,

Y. C. Park,

Hyunsoo Rho

et al.

JHEP Reports, Journal Year: 2025, Volume and Issue: unknown, P. 101414 - 101414

Published: April 1, 2025

Language: Английский

Citations

0
Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation DOI Creative Commons

Rola Al Sayegh,

Jinghong Wan, Charles Caër

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 24, 2025

Conventional CD4 T cells represent a major source of inflammatory mediators that drive progression chronic liver disease to fibrosis and end-stage cirrhosis. Identification cell pathways limits the response could thus have therapeutic relevance. Here we show, using both human samples mouse models, autophagy is deficient in from patients with advanced fibrosis, loss following genomic deletion ATG5 associated emergence pathogenic IL-17A + IFN-γ Th17 mice. Mechanistically, lacking display glycolytic phenotype enhanced type 3 cytokine (i.e., GM-CSF) release, shifting hepatic myofibroblasts, hepatocytes macrophages toward proinflammatory phenotype. We also show can be rescued extensive leading decreased frequency reduced GM-CSF levels; addition, limited observed mice which Rubicon, negative regulator autophagy, deleted specifically their cells. Our findings implicate as key target control inflammation-driven during injury.

Language: Английский

Citations

0