MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF

Wang, Xin; Ros, Uris; Agrawal, Deepti; Keller, Eva C.; Slotta‐Huspenina, Julia; Dill, Veronika; Shen, Bo; Shi, Run; Herold, Tobias; Belka, Claus; Misra, Ritu; Bassermann, Florian; García‐Sáez, Ana J.; Jost, Philipp J.

doi:10.1038/s41418-021-00811-1

Cited by 10 publications

(6 citation statements)

References 63 publications

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“…Inhibition of RIPK3 attenuated cardiac ischemia‒reperfusion injury [ 58 ] and sepsis [ 59 ] by reducing mitochondrial dysfunction, and inhibition of the RIPK1-RIPK3 pathway reduced tumor cell metastasis by decreasing vascular endothelial permeability [ 60 ]. Furthermore, MLKL attenuated colon inflammation and colitis tumorigenesis via suppression of inflammatory responses [ 17 ], inhibited intestinal tumorigenesis by suppressing the IL-6/JAK2/STAT3 pathway [ 61 ] and promoted cellular differentiation in myeloid leukemia by facilitating the release of G-CSF [ 18 ]. Inhibition of MLKL prevented obesity-induced insulin resistance in mice [ 20 ] and promoted intracellular Listeria replication [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, Nagy et al found that Ripk3 -/- mice were not protected from high-fat diet (HFD)-induced liver injury, whereas knockout of Mlkl exerted a protective effect [ 10 , 11 ], which suggested that the molecular machinery in the necroptotic pathway is complex and varies among diseases. In addition, multiple noncanonical mechanisms for RIPK3 and MLKL have been identified [ 12 – 20 ], some of which were even independent of inflammation and necroptosis [ 15 , 17 , 18 , 20 ]. The activation of RIPK3 [ 21 – 25 ] and MLKL [ 25 , 26 ] signaling were also involved in the pathogenesis of AP; however, their contribution to disease severity remains controversial.…”

Section: Introductionmentioning

confidence: 99%

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MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

Pan

Wang

et al. 2023

Cell Death Dis

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Acute pancreatitis (AP) is a disease characterized by local and systemic inflammation with an increasing incidence worldwide. Receptor-interacting serine/threonine protein kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), and innate immune cell macrophages have been reported to be involved in the pathogenesis of AP. However, the mechanisms by which RIPK3 and MLKL regulate pancreatic injury, as well as the interactions between injured pancreatic acinar cells and infiltrating macrophages in AP, remain poorly defined. In the present study, experimental pancreatitis was induced in C57BL/6J, Ripk3-/- and Mlkl-/- mice by cerulein plus lipopolysaccharide in vivo, and primary pancreatic acinar cells were also isolated to uncover cellular mechanisms during cerulein stimulation in vitro. The results showed that MLKL and its phosphorylated protein p-MLKL were upregulated in the pancreas of the mouse AP model and cerulein-treated pancreatic acinar cells, independent of its canonical upstream molecule Ripk3, and appeared to function in a cell death-independent manner. Knockout of Mlkl attenuated AP in mice by reducing the polarization of pancreatic macrophages toward the M1 phenotype, and this protective effect was partly achieved by reducing the secretion of CXCL10 from pancreatic acinar cells, whereas knockout of Ripk3 did not. In vitro neutralization of CXCL10 impaired the pro-M1 ability of the conditioned medium of cerulein-treated pancreatic acinar cells, whereas in vivo neutralization of CXCL10 reduced the polarization of pancreatic macrophages toward M1 and the severity of AP in mice. These findings suggested that targeting the MLKL-CXCL10-macrophage axis might be a promising strategy for the treatment of AP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

Pan

Wang

et al. 2023

Cell Death Dis

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“…It has been reported that cancer stem cells represent a subpopulation of cancer cells capable of self-renewal, tumor initiation, and therapeutic resistance [ 5 ]. In our previous study, we reported that the cancer stem cell population is highly resistant to chemotherapy due to its quiescence behavior [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Tumors are composed of different types of cells with different genetic, epigenetic and phenotypic background / properties, which can make them respond differently to different treatments [ 3 , 4 ]. Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess stem cell-like properties and are responsible for tumor initiation, maintenance, and resistance to therapy [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

SAA suppresses α-PD-1 induced anti-tumor immunity by driving TH2 polarization in lung adenocarcinoma

Wang,

Wen,

et al. 2023

Cell Death Dis

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Cancer stem cells (CSCs) are believed to be crucial in the initiation, progression, and recurrence of cancer. CSCs are also known to be more resistant to cancer treatments. However, the interaction between CSCs and the immune microenvironment is complex and not fully understood. In current study we used single cell RNA sequence (scRNA-Seq, public dataset) technology to identify the characteristic of CSCs. We found that the lung adenocarcinoma cancer stem population is highly inflammatory and remodels the tumor microenvironment by secreting inflammatory factors, specifically the acute phase protein serum amyloid A (SAA). Next, we developed an ex-vivo autologous patient-derived organoids (PDOs) and peripheral blood mononuclear cells (PBMCs) co-culture model to evaluate the immune biological impact of SAA. We found that SAA not only promotes chemoresistance by inducing cancer stem transformation, but also restricts anti-tumor immunity and promotes tumor fibrosis by driving type 2 immunity, and α-SAA neutralization antibody could restrict treatment resistant and tumor fibrosis. Mechanically, we found that the malignant phenotype induced by SAA is dependent on P2X7 receptor. Our data indicate that cancer stem cells secreted SAA have significant biological impact to promote treatment resistant and tumor fibrosis by driving cancer stemness transformation and type 2 immunity polarization via P2X7 receptor. Notably, α-SAA neutralization antibody shows therapeutic potential by restricting these malignant phenotypes.

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“…3) Remodeling microenvironment secretome, which not only promotes host immune tolerance but also might enhance tumor stemness / proliferation (e.g., regulating granulocyte colony-stimulating factor, IL-10, and IL-6, etc.) [7,8]. 4) Recruiting immunosuppressive cells in the microenvironment (e.g., myeloid-derived suppressor cells, regulatory T cells, etc.)…”

Section: Introductionmentioning

confidence: 99%

Peripheral blood lymphocytes differentiation patterns in responses / outcomes to immune checkpoint blockade therapies in non-small cell lung cancer: a retrospective study

Wen

Shi

et al. 2023

BMC Cancer

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Objectives Programmed Cell Death-1/ Programmed Death-ligand 1 (PD-1 / PD-L1) inhibitor therapies targeting immunocytes induce persistent tumor remission in various cancers. However, the appropriate biomarkers for the therapeutic efficacy of PD-L1 and PD-1 blockade remain elusive. Materials and methods For a comprehensive analysis of peri-treatment lymphocyte differentiation, in the current study, we enrolled 146 non-small cell lung cancer patients who received α-PD-1 therapies for exploring the peripheral blood lymphocyte differentiation pattern at baseline and post-treatment (dynamic changes) by flow cytometry. Results At baseline, CD4+ / CD8+ T cell ratio predicts good responses and outcomes, but activated T cell and cytotoxic T cell counts predict poor responses and outcomes. And for dynamic changes, after 6 weeks of immune checkpoint blockade (ICB) treatment, compared with baseline level, the elevation of total T and B cell counts indicate poor responses, and total T and TH cell counts indicate poor prognosis while activated T cell predicts good prognosis. And after 12 weeks, elevated total lymphocyte, cytotoxic T cell counts, and decreased total T cell counts and CD4+ / CD8+ T cell ratio predict good responses / outcomes. Our clinical predicting model shows good performance in predicting ICB treatment responses / outcomes. Conclusion Patients with favorable clinical responses / outcomes have distinctive peripheral blood immunocyte differentiation characteristics, indicating the potential of utilizing the peripheral immunocyte differentiation patterns for predicting ICB responses / outcomes.

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MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF

Cited by 10 publications

References 63 publications

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

SAA suppresses α-PD-1 induced anti-tumor immunity by driving TH2 polarization in lung adenocarcinoma

Peripheral blood lymphocytes differentiation patterns in responses / outcomes to immune checkpoint blockade therapies in non-small cell lung cancer: a retrospective study

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