PDF(Pubmed)
Abstract：
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.
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.
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+ 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.
UNASSIGNED: 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.
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.
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+ 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.
UNASSIGNED: 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.
摘要：
■代谢功能障碍相关脂肪性肝炎（MASH）是一个重要的健康问题，治疗选择有限。AXL,由GAS6配体激活的受体酪氨酸激酶，通过激活肝星状细胞和炎性巨噬细胞促进MASH。该研究鉴定了受MASH进展和AXL抑制的影响的细胞亚群。
■给小鼠喂食食物或不同的富含脂肪的饮食以诱导MASH，和小分子AXL激酶与bemcentinib的抑制作用进行评估。通过qPCR测量基因表达。飞行时间质谱（CyTOF）使用来自分离肝脏的单细胞，在FluidigmHelios上获得的，和细胞群体使用机器学习进行研究。
■在饲喂不同富含脂肪饮食的小鼠中，单纯肝脏脂肪变性不足以提高血浆可溶性AXL(sAXL)水平.然而,与炎症相结合，sAXL增加，作为脂肪性肝炎进展的早期指标。Bemcentinib,AXL抑制剂，有效减少MASH模型中的促炎反应，甚至在纤维化出现之前。利用CyTOF分析，我们检测到MASH期间Kupffer细胞数量减少，同时促进单核细胞/巨噬细胞和CD8+T细胞的浸润。Bemcentinib部分恢复了Kupffer细胞,减少pDC和GzMB-NK细胞，和增加GzmB+CD8+T细胞和LSEC。此外,AXL抑制增强了以CX3CR1表达为特征的GzmB+CD8+组织驻留记忆T细胞的亚型。此外，bemcentinib改变了与MASH进展相关的转录组景观，特别是在TLR信号和炎症反应中，在血浆中表现出差异的细胞因子表达，符合肝脏修复和炎症减少。
■我们的发现强调sAXL作为监测MASH进展的生物标志物，并证明AXL靶向肝巨噬细胞和CD8+T细胞亚群从炎症表型向纤维化消退和器官愈合转移，提出了一种有希望的MASH治疗策略。
■给小鼠喂食食物或不同的富含脂肪的饮食以诱导MASH，和小分子AXL激酶与bemcentinib的抑制作用进行评估。通过qPCR测量基因表达。飞行时间质谱（CyTOF）使用来自分离肝脏的单细胞，在FluidigmHelios上获得的，和细胞群体使用机器学习进行研究。
■在饲喂不同富含脂肪饮食的小鼠中，单纯肝脏脂肪变性不足以提高血浆可溶性AXL(sAXL)水平.然而,与炎症相结合，sAXL增加，作为脂肪性肝炎进展的早期指标。Bemcentinib,AXL抑制剂，有效减少MASH模型中的促炎反应，甚至在纤维化出现之前。利用CyTOF分析，我们检测到MASH期间Kupffer细胞数量减少，同时促进单核细胞/巨噬细胞和CD8+T细胞的浸润。Bemcentinib部分恢复了Kupffer细胞,减少pDC和GzMB-NK细胞，和增加GzmB+CD8+T细胞和LSEC。此外,AXL抑制增强了以CX3CR1表达为特征的GzmB+CD8+组织驻留记忆T细胞的亚型。此外，bemcentinib改变了与MASH进展相关的转录组景观，特别是在TLR信号和炎症反应中，在血浆中表现出差异的细胞因子表达，符合肝脏修复和炎症减少。
■我们的发现强调sAXL作为监测MASH进展的生物标志物，并证明AXL靶向肝巨噬细胞和CD8+T细胞亚群从炎症表型向纤维化消退和器官愈合转移，提出了一种有希望的MASH治疗策略。
