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1.
Blood ; 141(9): 1070-1086, 2023 03 02.
Article in English | MEDLINE | ID: mdl-36356302

ABSTRACT

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.


Subject(s)
Graft vs Host Disease , Intestines , Mice , Humans , Animals , Intestinal Mucosa/metabolism , Inflammation/metabolism , Histocompatibility Antigens Class II/metabolism , Graft vs Host Disease/prevention & control , Graft vs Host Disease/metabolism , Homeostasis , Receptor-Interacting Protein Serine-Threonine Kinases
2.
EMBO Rep ; 23(8): e54438, 2022 08 03.
Article in English | MEDLINE | ID: mdl-35735238

ABSTRACT

Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.


Subject(s)
Influenza A virus , MicroRNAs , Antiviral Agents , Humans , Interferons , MicroRNAs/genetics , MicroRNAs/metabolism , Necroptosis , Virus Replication/physiology
3.
Future Med Chem ; 14(6): 421-442, 2022 03.
Article in English | MEDLINE | ID: mdl-35167311

ABSTRACT

Background: Necroptosis is an important form of regulated cell death involved in inflammatory diseases, degenerative diseases and cancer. RIPK3 is an interesting target for intervention of necroptosis-associated diseases. Methodology: Herein the authors report the synthesis of a series RIPK3 inhibitors under the guidance of structure-based drug design which leads to the identification of compound 37. Results: Compound 37 potently rescued human and mouse cells from necroptotic stimuli TNF-α, Smac mimetic, z-VAD and LPS + z-VAD, displayed high affinity to RIPK3 (Kd = 14 nM) but no observable affinity to RIPK1 and inhibited RIPK3 kinase function. Importantly, compound 37 significantly alleviated TNF-induced systemic inflammatory response syndrome in the mouse model. Conclusion: These results support compound 37 as a prototype RIPK3 inhibitor for lead optimization.


Subject(s)
Drug Design , Necroptosis , Animals , Disease Models, Animal , Mice , Receptor-Interacting Protein Serine-Threonine Kinases , Tumor Necrosis Factor-alpha
4.
PeerJ ; 8: e8843, 2020.
Article in English | MEDLINE | ID: mdl-32219041

ABSTRACT

PURPOSE: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma that is incurable with standard therapies. The use of gene expression analysis has been of interest, recently, to detect biomarkers for cancer. There is a great need for systemic coexpression network analysis of MCL and this study aims to establish a gene coexpression network to forecast key genes related to the pathogenesis and prognosis of MCL. METHODS: The microarray dataset GSE93291 was downloaded from the Gene Expression Omnibus database. We systematically identified coexpression modules using the weighted gene coexpression network analysis method (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were performed on the modules deemed important. The protein-protein interaction networks were constructed and visualized using Cytoscape software on the basis of the STRING website; the hub genes in the top weighted network were identified. Survival data were analyzed using the Kaplan-Meier method and were compared using the log-rank test. RESULTS: Seven coexpression modules consisting of different genes were applied to 5,000 genes in the 121 human MCL samples using WGCNA software. GO and KEGG enrichment analysis identified the blue module as one of the most important modules; the most critical pathways identified were the ribosome, oxidative phosphorylation and proteasome pathways. The hub genes in the top weighted network were regarded as real hub genes (IL2RB, CD3D, RPL26L1, POLR2K, KIF11, CDC20, CCNB1, CCNA2, PUF60, SNRNP70, AKT1 and PRPF40A). Survival analysis revealed that seven genes (KIF11, CDC20, CCNB1, CCNA2, PRPF40A, CD3D and PUF60) were associated with overall survival time (p < 0.05). CONCLUSIONS: The blue module may play a vital role in the pathogenesis of MCL. Five real hub genes (KIF11, CDC20, CCNB1, CCNA2 and PUF60) were identified as potential prognostic biomarkers as well as therapeutic targets with clinical utility for MCL.

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