Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH.
Animals
Axl Receptor Tyrosine Kinase
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Mice
Proto-Oncogene Proteins
/ antagonists & inhibitors
Liver Cirrhosis
/ immunology
Male
Disease Models, Animal
Mice, Inbred C57BL
Benzocycloheptenes
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Liver
/ pathology
Macrophages
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Triazoles
GAS6
MERTK
TAM receptors
immune response
inflammation
liver fibrosis
mass cytometry
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2024
2024
Historique:
received:
13
03
2024
accepted:
23
04
2024
medline:
31
5
2024
pubmed:
31
5
2024
entrez:
31
5
2024
Statut:
epublish
Résumé
Metabolic dysfunction-associated steatohepatitis (MASH) is a significant health concern with limited treatment options. AXL, a receptor tyrosine kinase activated by the GAS6 ligand, promotes MASH through activation of hepatic stellate cells and inflammatory macrophages. This study identified cell subsets affected by MASH progression and the effect of AXL inhibition. Mice were fed chow or different fat-enriched diets to induce MASH, and small molecule AXL kinase inhibition with bemcentinib was evaluated. Gene expression was measured by qPCR. Time-of-flight mass cytometry (CyTOF) used single cells from dissociated livers, acquired on the Fluidigm Helios, and cell populations were studied using machine learning. In mice fed different fat-enriched diets, liver steatosis alone was insufficient to elevate plasma soluble AXL (sAXL) levels. However, in conjunction with inflammation, sAXL increases, serving as an early indicator of steatohepatitis progression. Bemcentinib, an AXL inhibitor, effectively reduced proinflammatory responses in MASH models, even before fibrosis appearance. Utilizing CyTOF analysis, we detected a decreased population of Kupffer cells during MASH while promoting infiltration of monocytes/macrophages and CD8 Our findings highlight sAXL as a biomarker for monitoring MASH progression and demonstrate that AXL targeting shifted liver macrophages and CD8
Sections du résumé
Background and aims
UNASSIGNED
Metabolic dysfunction-associated steatohepatitis (MASH) is a significant health concern with limited treatment options. AXL, a receptor tyrosine kinase activated by the GAS6 ligand, promotes MASH through activation of hepatic stellate cells and inflammatory macrophages. This study identified cell subsets affected by MASH progression and the effect of AXL inhibition.
Methods
UNASSIGNED
Mice were fed chow or different fat-enriched diets to induce MASH, and small molecule AXL kinase inhibition with bemcentinib was evaluated. Gene expression was measured by qPCR. Time-of-flight mass cytometry (CyTOF) used single cells from dissociated livers, acquired on the Fluidigm Helios, and cell populations were studied using machine learning.
Results
UNASSIGNED
In mice fed different fat-enriched diets, liver steatosis alone was insufficient to elevate plasma soluble AXL (sAXL) levels. However, in conjunction with inflammation, sAXL increases, serving as an early indicator of steatohepatitis progression. Bemcentinib, an AXL inhibitor, effectively reduced proinflammatory responses in MASH models, even before fibrosis appearance. Utilizing CyTOF analysis, we detected a decreased population of Kupffer cells during MASH while promoting infiltration of monocytes/macrophages and CD8
Conclusion
UNASSIGNED
Our findings highlight sAXL as a biomarker for monitoring MASH progression and demonstrate that AXL targeting shifted liver macrophages and CD8
Identifiants
pubmed: 38817615
doi: 10.3389/fimmu.2024.1400553
pmc: PMC11137289
doi:
Substances chimiques
Axl Receptor Tyrosine Kinase
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Proto-Oncogene Proteins
0
bemcentinib
0ICW2LX8AS
AXL receptor tyrosine kinase, mouse
0
Benzocycloheptenes
0
Protein Kinase Inhibitors
0
Triazoles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1400553Informations de copyright
Copyright © 2024 Grøndal, Tutusaus, Boix, Reig, Blø, Hodneland, Gausdal, Jackson, Garcia de Frutos, Lorens, Morales and Marí.
Déclaration de conflit d'intérêts
These authors disclose the following: JL is a co-founder of BerGenBio. MB, LH, and GG were employed by BerGenBio. AJ is employed by BerGenBio. PG, MM, and AM received research funding from BerGenBio. MR has served as a consultant or on advisory boards: AstraZeneca, Bayer, BMS, Eli Lilly, Geneos, Ipsen, Merck, Roche, Universal DX; Speaking: AstraZeneca, Bayer, BMS, Eli Lilly, Gilead, ROCHE; Grant Research Support to the institution: Bayer, Ipsen; Educational Support to the institution: Bayer AstraZeneca, Eisai-MSD, ROCHE, Ipsen, Eli Lilly, Terumo, Next, Boston, Scientific, Ciscar Medical; Principal or sub-investigator of a drug under development: AbbVie, BMS, Adaptimmune, Nerviano, Bayer, Ipsen, AstraZeneca, Terumo, Incyte, ROCHE, Boston Scientific; Travel support: Terumo, AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.