TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury

Vyrla, Dimitra; Nikolaidis, George; Oakley, Fiona; Tsichlis, Philip N.; Mann, Derek A.; Eliopoulos, Aristides G.

doi:10.4049/jimmunol.1501609

Cited by 13 publications

(6 citation statements)

References 46 publications

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“…10f). To test for MAPK pathway involvement in ALF, we selected six proteins from the pathway for which small molecule inhibitors are available: IRAK4, RIP1, TAK1, TPL2, ERK1/2 and p38, and tested them in APAP-induced ALF [45][46][47][48][49][50] . Indeed, we observed significant reduction of monocyte infiltration in mice receiving inhibitors of IRAK4, TAK1 and p38 (Fig.…”

Section: Tlr Signaling and Downstream Adapters Are Necessary For Activation Of The Myc Program In Alfmentioning

confidence: 99%

Acute liver failure is regulated by MYC- and microbiome-dependent programs

Kolodziejczyk¹,

Federici²,

Zmora³

et al. 2020

Nat Med

112

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Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.

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Section: Tlr Signaling and Downstream Adapters Are Necessary For Activation Of The Myc Program In Alfmentioning

confidence: 99%

Acute liver failure is regulated by MYC- and microbiome-dependent programs

Kolodziejczyk¹,

Federici²,

Zmora³

et al. 2020

Nat Med

112

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“…ANXA1, among other secreted molecules by AF-MSCs, may offer protective effects of AF-MSCs in acute liver injury. As liver injury is accompanied by a systemic inflammatory response [39], we asked if the ANXA1 effects on AHF, entail regulation of inflammatory cytokine expression. To address this question, we assessed serum levels of pro-inflammatory IFNγ and TNF and of anti-inflammatory IL-10 in AHF mice administered CM isolated from either AF-MSC-shscramble or AF-MSC-shANXA1 cultures.…”

Section: Resultsmentioning

confidence: 99%

Functional secretome analysis reveals Annexin-A1 as important paracrine factor derived from fetal mesenchymal stem cells in hepatic regeneration

et al. 2019

Self Cite

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Background: Human mesenchymal stem/stromal cells (MSCs) and their secreted molecules exert beneficial effects in injured tissues by promoting tissue regeneration and angiogenesis and by inhibiting inflammation and fibrosis. We have previously demonstrated that the therapeutic activity of fetal MSCs derived from amniotic fluid (AF-MSCs) and their hepatic progenitor-like cells (HPL) is mediated by paracrine effects in a mouse model of acute hepatic failure (AHF). Methods: Herein, we have combined proteomic profiling of the AF-MSCs and HPL cell secretome with ex vivo and in vivo functional studies to identify specific soluble factors, which underpin tissue regeneration in AHF. Findings: The anti-inflammatory molecule Annexin-A1 (ANXA1) was detected at high levels in both AF-MSC and HPL cell secretome. Further functional analyses revealed that the shRNA-mediated knock-down of ANXA1 in MSCs (shANXA1-MSCs) decreased their proliferative, clonogenic and migratory potential, as well as their ability to differentiate into HPL cells. Liver progenitors (oval cells) from AHF mice displayed reduced proliferation when cultured ex vivo in the presence of conditioned media from shANXA1-MSCs compared to control MSCs secretome. Intra-hepatic delivery of conditioned media from control MSCs but not shANXA1-MSCs reduced liver damage and circulating levels of pro-inflammatory cytokines in AHF. Interpretation: Collectively, our study uncovers secreted Annexin-A1 as a novel effector of MSCs in liver regeneration and further underscores the potential of cell-free therapeutic strategies for liver diseases.

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“…This process is different from the development of traditional T cells 16 . In addition, antigens involved in the selection of iNKTs have a strong affinity for TCR‐β and determine the phenotype of iNKTs (CD1d + and TCR‐β + ), which is also used as the standard method for screening iNKTs in the previous studies 17,18 . The development of iNKTs is a multistep process.…”

Section: Development and Differentiation Of Invariant Natrual Killer mentioning

confidence: 99%

Invariant natural killer T cells: Not to be ignored in liver disease

Gan

Mao

Zheng

et al. 2021

J of Digest Diseases

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The liver is an important immune organ. Hepatocellular injury can be caused by many factors, which further leads to chronic liver diseases by activating the immune system. Multiple immune cells, such as T lymphocytes, B lymphocytes, natural killer cells (NKs), natural killer T cells (NKTs), and γδT cells, accumulate and participate in the immune regulation of the liver. NKTs are an indispensable component of immune cells in the liver, and invariant natural killer T cells (iNKTs) are the main subpopulation of NKTs. iNKTs activated by glycolipid antigen presented on CD1d secrete a series of cytokines and also act on other immune cells through cell‐to‐cell contact. Studies on the relationship between iNKTs and liver immunity have provided clues to uncover the pathogenesis of liver diseases and develop a promising strategy for the diagnosis and treatment of liver diseases.

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TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury

Cited by 13 publications

References 46 publications

Acute liver failure is regulated by MYC- and microbiome-dependent programs

Acute liver failure is regulated by MYC- and microbiome-dependent programs

Functional secretome analysis reveals Annexin-A1 as important paracrine factor derived from fetal mesenchymal stem cells in hepatic regeneration

Invariant natural killer T cells: Not to be ignored in liver disease

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