Modulating T-cell activation with antisense oligonucleotides targeting lymphocyte cytosolic protein 2

Iyer, Vaishnavi Srinivasan; Boddul, Sanjaykumar V.; Johnsson, Anna‐Karin; Raposo, Bruno; Sharma, Ravi; Shen, Yunbing; Kasza, Zsolt; Lim, Kah Wai; Chemin, Karine; Nilsson, Gunnar; Malmström, Vivianne; Phan, Anh Tuân; Wermeling, Fredrik

doi:10.1016/j.jaut.2022.102857

Cited by 9 publications

(2 citation statements)

References 57 publications

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“…In the present study, we found eight key genes involved in cholestasis, and all of them were highly immune-associated. Among them, SYK, PTPRC, TYROBP, LCP2, and CD53 are preferentially expressed on various adaptive immune cells, playing an important role in the activation of T cells and B cells ( Donovan and Koretzky, 1993 ; Cornall et al, 2000 ; Dunlock et al, 2022 ; Iyer et al, 2022 ). Simultaneously, emerging evidence showed that SYK was required for monocyte adhesion ( Chang et al, 2012 ) and was related to the phenotype switch of monocyte-derived macrophages ( Chen et al, 2021 ), playing an indispensable role in innate immunity.…”

Section: Discussionmentioning

confidence: 99%

Uncovering key molecules and immune landscape in cholestatic liver injury: implications for pathogenesis and drug therapy

Song

Geng

et al. 2023

Front. Pharmacol.

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Background: Cholestasis is a common pathological process in a variety of liver diseases that may lead to liver fibrosis, cirrhosis, and even liver failure. Cholestasis relief has been regarded as a principal target in the management of multiple chronic cholestasis liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) at present. However, complicated pathogenesis and limited acknowledgments fettered therapeutic development. Therefore, this study aimed to systematically analyze miRNA-mRNA regulatory networks in cholestatic liver injury in order to provide new treatment strategies.Methods: Gene Expression Omnibus (GEO) database (GSE159676) was used to screen differentially expressed hepatic miRNAs and mRNAs in the PSC vs. control comparison and the PBC vs. control comparison, respectively. MiRWalk 2.0 tool was used to predict miRNA-mRNA pairs. Subsequently, functional analysis and immune cell infiltration analysis were performed to explore the pivotal functions of the target genes. RT-PCR was used to verify the result.Results: In total, a miRNA-mRNA network including 6 miRNAs (miR-122, miR-30e, let-7c, miR-107, miR-503, and miR-192) and 8 hub genes (PTPRC, TYROBP, LCP2, RAC2, SYK, TLR2, CD53, and LAPTM5) was constructed in cholestasis. Functional analysis revealed that these genes were mainly involved in the regulation of the immune system. Further analysis revealed that resting memory CD4 T cells and monocytes could potentially participate in cholestatic liver injury. The expressions of DEMis and eight hub genes were verified in ANIT-induced and BDL-induced cholestatic mouse models. Furthermore, SYK was found to have an impact on the response to UDCA, and its mechanism was possibly associated with complement activation and monocyte reduction.Conclusion: In the present study, a miRNA-mRNA regulatory network was constructed in cholestatic liver injury, which mostly mediated immune-related pathways. Moreover, the targeted gene SYK and monocytes were found to be related to UDCA response in PBC.

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Section: Discussionmentioning

confidence: 99%

Uncovering key molecules and immune landscape in cholestatic liver injury: implications for pathogenesis and drug therapy

Song

Geng

et al. 2023

Front. Pharmacol.

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“…Regarding the use of EVs as biomarkers of exposure, there were 65 proteins that were significantly altered across all the doses and timepoints ( Tables 1 , 2 ). Among the proteins that had the highest fold-change across all groups were thromboxane A synthase and lymphocyte cytosolic protein 2 which play essential roles in platelet function and T-cell receptor signaling, respectively ( 52 , 53 ). Among proteins decreased across all groups, the transforming growth factor, vasorin, was significantly decreased ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction

et al. 2023

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Acute radiation syndrome (ARS) develops after exposure to high doses of ionizing radiation and features immune suppression and organ failure. Currently, there are no diagnostics to identify the occurrence or severity of exposure and there are limited treatments and preventative strategies to mitigate ARS. Extracellular vesicles (EVs) are mediators of intercellular communication that contribute to immune dysfunction across many diseases. We investigated if EV cargo can identify whole body irradiation (WBIR) exposure and if EVs promote ARS immune dysfunction. We hypothesized that beneficial EVs derived from mesenchymal stem cells (MSC-EVs) would blunt ARS immune dysfunction and might serve as prophylactic radioprotectants. Mice received WBIR (2 or 9 Gy) with assessment of EVs at 3 and 7 days after exposure. LC-MS/MS proteomic analysis of WBIR-EVs found dose-related changes as well as candidate proteins that were increased with both doses and timepoints (34 total) such as Thromboxane-A Synthase and lymphocyte cytosolic protein 2. Suprabasin and Sarcalumenin were increased only after 9 Gy suggesting these proteins may indicate high dose/lethal exposure. Analysis of EV miRNAs identified miR-376 and miR-136, which were increased up to 200- and 60-fold respectively by both doses of WBIR and select miRNAs such as miR-1839 and miR-664 were increased only with 9 Gy. WBIR-EVs (9 Gy) were biologically active and blunted immune responses to LPS in RAW264.7 macrophages, inhibiting canonical signaling pathways associated with wound healing and phagosome formation. When given 3 days after exposure, MSC-EVs slightly modified immune gene expression changes in the spleens of mice in response to WBIR and in a combined radiation plus burn injury exposure (RCI). MSC-EVs normalized the expression of certain key immune genes such as NFκBia and Cxcr4 (WBIR), Map4k1, Ccr9 and Cxcl12 (RCI) and lowered plasma TNFα cytokine levels after RCI. When given prophylactically (24 and 3 hours before exposure), MSC-EVs prolonged survival to the 9 Gy lethal exposure. Thus, EVs are important participants in ARS. EV cargo might be used to diagnose WBIR exposure, and MSC-EVs might serve as radioprotectants to blunt the impact of toxic radiation exposure.

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Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy

Jin,

Tu,

et al. 2024

International Immunopharmacology

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Modulating T-cell activation with antisense oligonucleotides targeting lymphocyte cytosolic protein 2

Cited by 9 publications

References 57 publications

Uncovering key molecules and immune landscape in cholestatic liver injury: implications for pathogenesis and drug therapy

Uncovering key molecules and immune landscape in cholestatic liver injury: implications for pathogenesis and drug therapy

Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction

Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy

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