Dead Cells Induce Innate Anergy Via Mertk after Acute Viral Infection

Adomati, Tom; Duhan, Vikas; Hamdan, Thamer A; Cham, Lamin B.; Bhat, Hilal; Li, Fangui; Lang, Elisabeth; Khairnar, Vishal; Friedrich, Sarah-Kim; Friebus‐Kardash, Justa; Bezgovsek, Judith; Bergerhausen, Michael; Schiller, Maximilian; Maria, Machlah Yara; Ali, Murtaza; Läng, Florian; Häussinger, Dieter; Ferenčík, Stanislav; Hardt, Cornelia; Lang, Philipp A.; Lang, Karl S.

doi:10.2139/ssrn.3426159

Cited by 2 publications

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“…Although MerTK implication in immunosuppression is known, its mechanism remains unclear. It had been reported previously that MerTK- or PROS1-deficient mice display lower levels of IL-10 production by myeloid cells following bacterial or viral activation, or in cancer models ( 18 , 32 , 33 ). We present evidence that MerTK activation by its ligand PROS1 induces IL-10 production in human tolerogenic DC following TLR4 activation.…”

Section: Discussionmentioning

confidence: 91%

Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC

et al. 2020

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Tumor-infiltrating myeloid cells are a key component of the immune infiltrate often correlated with a poor prognosis due to their capacities to sustain an immunosuppressive environment. Among membrane receptors implicated in myeloid cell functions, Tyro3, Axl, and MerTK, which are a family of tyrosine kinase receptors (TAM-R), have been described in the regulation of innate cell functions. Here, we have identified MerTK among TAM-R as the major marker of both human M2 macrophages and tolerogenic dendritic cells (DC). In situ, MerTK expression was found within the immune infiltrate in multiple solid tumors, highlighting its potential role in cancer immunity. TAM-R ligands Gas6 and PROS1 were found to be constitutively produced by myeloid cells in vitro. Importantly, we describe a novel function of MerTK/PROS1 axis in the regulation of IL-10 production by tolerogenic DC. Finally, the analysis of TAM-R expression within the lymphoid compartment following activation revealed that MerTK, but not Axl or Tyro3, is expressed on activated B lymphocytes and regulatory T cells, as well as CD4 + and CD8 + T cells. Thus, our findings deepen the implication of MerTK in the regulation of myeloid cell-mediated immunosuppression and identified new cellular targets expressing MerTK that could participate in the antitumor immune response.

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Section: Discussionmentioning

confidence: 91%

Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC

et al. 2020

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“…Interestingly, efferocytosis by APCs is associated with induction of T-cell anergy [ 53 ] mediated, in part, through TAM signaling. After pre-treatment with apoptotic cells, MERTK inhibits the NF-κB pathway, reducing the secretion of pro-inflammatory cytokines [ 54 , 55 ] and induces an immunosuppressive profile, characterized by high interleukin-10 (IL-10) and transforming growth factor-beta (TGFβ) and low type I IFN levels [ 56 ]. In fact, Mertk−/− mice displayed low levels of IL-10 and TGF-β after vesicular stomatitis virus (VSV) infection, resulting in abrogation of innate anergy, which is associated with enhanced VSV replication and poor survival after infection [ 56 ].…”

Section: Tam Receptor Functionsmentioning

confidence: 99%

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

Tutusaus

Marı́

Ortiz-Pérez

et al. 2020

Cells

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The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.

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Dead Cells Induce Innate Anergy Via Mertk after Acute Viral Infection

Cited by 2 publications

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Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC

Expression of TAM-R in Human Immune Cells and Unique Regulatory Function of MerTK in IL-10 Production by Tolerogenic DC

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

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