Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH

Magnus Grøndal, Sturla; Tutusaus, Anna; Boix, Loreto; Reig, María; Blø, Magnus; Hodneland, Linn; Gausdal, Gro; Jackson, Akil; García de Frutos, Pablo; Lorens, James Bradley; Morales, Albert; Marí, Montserrat

Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH

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dc.contributor.author Magnus Grøndal, Sturla
dc.contributor.author Tutusaus, Anna
dc.contributor.author Boix, Loreto
dc.contributor.author Reig, María
dc.contributor.author Blø, Magnus
dc.contributor.author Hodneland, Linn
dc.contributor.author Gausdal, Gro
dc.contributor.author Jackson, Akil
dc.contributor.author García de Frutos, Pablo
dc.contributor.author Lorens, James Bradley
dc.contributor.author Morales, Albert
dc.contributor.author Marí, Montserrat
dc.date.accessioned 2025-05-27T06:29:25Z
dc.date.available 2025-05-27T06:29:25Z
dc.date.issued 2024
dc.description.abstract Background and aims: 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: 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: 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+ T cells. Bemcentinib partially restored Kupffer cells, reduced pDCs and GzmB- NK cells, and increased GzmB+CD8+ T cells and LSECs. Additionally, AXL inhibition enhanced a subtype of GzmB+CD8+ tissue-resident memory T cells characterized by CX3CR1 expression. Furthermore, bemcentinib altered the transcriptomic landscape associated with MASH progression, particularly in TLR signaling and inflammatory response, exhibiting differential cytokine expression in the plasma, consistent with liver repair and decreased inflammation. Conclusion: Our findings highlight sAXL as a biomarker for monitoring MASH progression and demonstrate that AXL targeting shifted liver macrophages and CD8+ T-cell subsets away from an inflammatory phenotype toward fibrotic resolution and organ healing, presenting a promising strategy for MASH treatment.
dc.description.sponsorship The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Projects# RTI2018–095672-B-I00 and PID2021–123564OB-I00 to AM and PG funded by MCIN/AEI/10.13039/501100011033 and co-funded by “ERDF A way of making Europe”. Project# PI19/01410 and PI22/00475 to MM funded by Instituto de Salud Carlos III and co-funded by the European Union “ERDF A way of making Europe”; AGAUR (2021_SGR_490) and CERCA Programme/Generalitat de Catalunya, and Fundació la Marató de TV3 (202133–32).
dc.format.mimetype application/pdf
dc.identifier.citation Grøndal SM, Tutusaus A, Boix L, Reig M, Blø M, Hodneland L, et al. Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH. Front Immunol. 2024 May 16;15:1400553. DOI: 10.3389/fimmu.2024.1400553
dc.identifier.doi http://dx.doi.org/10.3389/fimmu.2024.1400553
dc.identifier.issn 1664-3224
dc.identifier.uri http://hdl.handle.net/10230/70517
dc.language.iso eng
dc.publisher Frontiers
dc.relation.ispartof Front Immunol. 2024 May 16;15:1400553
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021–123564OB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018–095672-B-I00
dc.rights © 2024 Grøndal, Tutusaus, Boix, Reig, Blø, Hodneland, Gausdal, Jackson, Garcia de Frutos, Lorens, Morales and Marí. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. http://creativecommons.org/licenses/by/4.0/
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword GAS6
dc.subject.keyword MERTK
dc.subject.keyword TAM receptors
dc.subject.keyword Immune response
dc.subject.keyword Inflammation
dc.subject.keyword Liver fibrosis
dc.subject.keyword Mass cytometry
dc.title Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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