Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

Brenig, Robert; Pop, Oltin T.; Triantafyllou, Evangelos; Geng, Anne; Singanayagam, Arjuna; Pérez-Shibayama, Christian; Bešše, Lenka; Cupovic, Jovana; Künzler, Patrizia; Boldanova, Tuyana; Brand, Stephan; Semela, David; Duong, François H. T.; Weston, Chris J.; Ludewig, Burkhard; Heim, Markus H.; Wendon, Julia; Antoniades, Charalambos; Bernsmeier, Christine

doi:10.26508/lsa.201900465

Cited by 31 publications

(84 citation statements)

References 52 publications

(113 reference statements)

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“… 51 , 52 ) and are the main precipitant for hepatic acute decompensation (AD), with or without organ failure (acute-on-chronic liver failure [ACLF]) ( 53 , 54 ). Like ALF ( 3 ), cirrhosis and ACLF are associated with inflammation and, as disease progresses, immune dysfunction that contribute to increased susceptibility to infection ( 5 , 8 , 55 – 57 ). It would be important to further investigate the significance of the PD-1/PD-L1 pathway in cirrhosis, AD, and ACLF and its contribution to systemic and hepatic immune suppression.…”

Section: Discussionmentioning

confidence: 99%

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury

Triantafyllou¹,

Gudd²,

Mawhin³

et al. 2021

Journal of Clinical Investigation

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Patients with acute liver failure (ALF) have systemic innate immune suppression and increased susceptibility to infections. Programmed cell death 1 (PD-1) expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in regulating Kupffer cell (KC) inflammatory and antimicrobial responses in acetaminophen-induced (APAP-induced) acute liver injury. Using intravital imaging and flow cytometry, we found impaired KC bacterial clearance and systemic bacterial dissemination in mice with liver injury. We detected increased PD-1 and PD-L1 expression in KCs and lymphocyte subsets, respectively, during injury resolution. Gene expression profiling of PD-1 + KCs revealed an immune-suppressive profile and reduced pathogen responses. Compared with WT mice, PD-1–deficient mice and anti–PD-1–treated mice with liver injury showed improved KC bacterial clearance, a reduced tissue bacterial load, and protection from sepsis. Blood samples from patients with ALF revealed enhanced PD-1 and PD-L1 expression by monocytes and lymphocytes, respectively, and that soluble PD-L1 plasma levels could predict outcomes and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for the PD-1/PD-L1 axis in suppressing KC and monocyte antimicrobial responses after liver injury and identifies anti–PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.

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Section: Discussionmentioning

confidence: 99%

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury

Triantafyllou¹,

Gudd²,

Mawhin³

et al. 2021

Journal of Clinical Investigation

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“…Furthermore, there is evidence that AXL-CAR-T cell therapy has the potential to overcome the immunosuppressive TME by inhibiting the release of suppressive chemokines and cytokines from TAMs (67,68). In addition, since AXL expression is found on MDSCs, it is possible that CAR-T cells targeting AXL may deplete MDSCs from the TME and fundamentally alter the TME to a proinflammatory state (69). More recently, it was demonstrated that AXL-CAR-T cells with constitutive expression of the IL-7 receptor had enhanced in vitro anti-tumor activity and prolonged survival in a TNBC subcutaneous xenograft model (70).…”

Section: Receptor Tyrosine Kinase Axlmentioning

confidence: 99%

“…For example, expression of antigenic targets on both TNBC primary tumors and cells residing in the TME (e.g. MDSCs, TAMs, CAFs, Tregs), can facilitate CAR-T cell directed targeting of multiple cell types to overcome the immunosuppressive TME and enhance anti-tumor activity (69,76,94).…”

Section: Future Perspectives and Concluding Remarksmentioning

confidence: 99%

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

Dees

Ganesan

Singh

et al. 2020

Molecular Cancer Therapeutics

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“…With respect to Axl, elevated serum levels of soluble Axl extracellular domain (sAxl) have been found to be a biomarker for hepatocellular carcinoma (Reichl & Mikulits, 2016), and mice lacking Gas6, the obligate Axl ligand (Lew et al, 2014), display enhanced tissue damage in a liver ischemia model (Llacuna et al, 2010). At the same time, Axl + monocytes are elevated in patients with cirrhosis (Brenig et al, 2020), and serum Gas6 and sAxl levels are elevated in patients with hepatitis C virus and alcoholic liver disease (Barcena et al, 2015). Divergent roles for Axl and Mer have been reported in chronic models of fibrosis, where Mertk −/− mice exhibited enhanced NASH development when fed a high-fat diet, whereas Axl −/− mice were protected (Tutusaus et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

et al. 2020

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Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

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Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

Abstract: Immune dysfunction determines morbidity and mortality in liver cirrhosis. Distinct AXL-expressing circulating monocytes, which regulate antimicrobial responses, expand with progression of the disease.

Cited by 31 publications

References 52 publications

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

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