IGSF3 mutation identified in patient with severe COPD alters cell function and motility

Schweitzer, Kelly S.; Jinawath, Natini; Yonescu, Raluca; Ni, Kevin; Rush, Natalia; Charoensawan, Varodom; Berdyshev, Evgeny; Leach, Sonia M.; Gillenwater, Lucas A.; Bowler, R.P.; Pearse, David B.; Griffin, Constance A.; Petrache, Irina

doi:10.1172/jci.insight.138101

Cited by 5 publications

(8 citation statements)

References 41 publications

(46 reference statements)

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“…These were Ahr (aryl hydrocarbon receptor), Ca13 (carbonic anhydrase 13), Epo (erythropoietin), Igsf3 (immunoglobulin superfamily member 3), IL-1a (interleukin 1a), Tnfrsf12a [tumor necrosis factor (TNF) ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK)], Crim1 (cysteine-rich motor neuron 1), and Tnr (tenascin-R). These shifts in virally induced serum proteins may reflect responses to hypoxia [Epo ( 35 ), IL-1a ( 36 ), Ahr ( 37 )], changes in angiogenesis [Crim1 ( 38 ), Tnfrsf12a ( 39 )], inflammation [Ahr ( 40 ), IL-1a ( 36 ), Tnfrsf12a ( 39 )], or cell adhesion [Tnfrs12a and Igsf3 ( 41 )], and additional responses not yet fully explored [Ca13 ( 42 )].…”

Section: Resultsmentioning

confidence: 99%

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Curran,

Cui,

et al. 2024

Front. Immunol.

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IntroductionBecause prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). MethodsIn Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production.ResultsStudy 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. DiscussionIn Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

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Section: Resultsmentioning

confidence: 99%

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Curran,

Cui,

et al. 2024

Front. Immunol.

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“…Then, we hypothesized that the homophilic interaction of IGSF3 mediates the adhesion of B16F10 cells to the vECs, given that IGSF3 is reported to be expressed in lung vECs 20 . MS1 mouse vECs also expressed Igsf3 mRNA, and introduction of siRNA against Igsf3 in MS1 markedly reduced its expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…IGSF3 belongs to the EWI subfamily of the IgSF and is characterized by a Glu-Trp-Ile (EWI) motif. IGSF3 forms a complex on the plasma membrane with tetraspanins through this motif and plays critical roles such as maintaining sphingolipid homeostasis during repair after lung injury and regulating cerebellar granule cell differentiation in neuronal morphogenesis 20, 21 . However, the physiological roles of IGSF3 are not well understood, and its function in mediating intercellular interactions has not yet been recognized.…”

Section: Discussionmentioning

confidence: 99%

IGSF3 is a homophilic cell adhesion molecule that drives lung metastasis of melanoma by promoting adhesion to vascular endothelium

Guo,

Kasai,

Tanaka

et al. 2023

Preprint

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The immunoglobulin superfamily (IgSF) is one of the largest families of cell-surface molecules involved in various cell-cell interactions, including cancer-stromal interactions. In this study, we conducted a comprehensive RT-PCR-based screening for IgSF molecules that promote experimental lung metastasis in mice. By comparing the expression of 325 genes encoding cell-surface IgSF molecules between mouse melanoma B16 cells and its highly metastatic subline, B16F10 cells, we found that expression of theImmunoglobulin superfamily member 3(Igsf3) was significantly enhanced in B16F10 cells than in B16 cells. Knockdown ofIgsf3in B16F10 cells significantly reduced lung metastasis following intravenous injection into C57BL/6 mice. IGSF3 promoted adhesion of B16F10 cells to vascular endothelial cells and functioned as a homophilic cell adhesion molecule between B16F10 cells and vascular endothelial cells. Notably, the knockdown of IGSF3 in either B16F10 cells or vascular endothelial cells suppressed the transendothelial migration of B16F10 cells. Moreover, IGSF3 knockdown suppressed the extravasation of B16F10 cells into the lungs after intravenous injection. These results suggest that IGSF3 promotes the metastatic potential of B16F10 cells in the lungs by facilitating their adhesion to vascular endothelial cells.

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“…IGSF3 forms a complex on the plasma membrane with tetraspanins through this motif and plays critical roles such as maintaining sphingolipid homeostasis during repair after lung injury and regulating cerebellar granule cell differentiation in neuronal morphogenesis. 22,23 However, the physiological roles of IGSF3 are not well understood, and its function in mediating intercellular interac- This process requires the expression of ligand-receptor pairs between cancer cells and vECs. 24 Most cell adhesion molecules, including selectins, integrins, cadherins, and IgSF cell adhesion molecules (IgCAMs), have been implicated in this process.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that the homophilic interaction of IGSF3 mediates the adhesion of B16F10 cells to the vECs, given that IGSF3 is reported to be expressed in lung vECs. 22…”

Section: Homophilic Interaction Of Igsf3 Promotes Extravasation Of B1...mentioning

confidence: 99%

IGSF3 is a homophilic cell adhesion molecule that drives lung metastasis of melanoma by promoting adhesion to vascular endothelium

Guo,

Kasai,

Tanaka

et al. 2024

Cancer Science

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The immunoglobulin superfamily (IgSF) is one of the largest families of cell‐surface molecules involved in various cell–cell interactions, including cancer–stromal interactions. In this study, we undertook a comprehensive RT‐PCR‐based screening for IgSF molecules that promote experimental lung metastasis in mice. By comparing the expression of 325 genes encoding cell‐surface IgSF molecules between mouse melanoma B16 cells and its highly metastatic subline, B16F10 cells, we found that expression of the immunoglobulin superfamily member 3 gene (Igsf3) was significantly enhanced in B16F10 cells than in B16 cells. Knockdown of Igsf3 in B16F10 cells significantly reduced lung metastasis following intravenous injection into C57BL/6 mice. IGSF3 promoted adhesion of B16F10 cells to vascular endothelial cells and functioned as a homophilic cell adhesion molecule between B16F10 cells and vascular endothelial cells. Notably, the knockdown of IGSF3 in either B16F10 cells or vascular endothelial cells suppressed the transendothelial migration of B16F10 cells. Moreover, IGSF3 knockdown suppressed the extravasation of B16F10 cells into the lungs after intravenous injection. These results suggest that IGSF3 promotes the metastatic potential of B16F10 cells in the lungs by facilitating their adhesion to vascular endothelial cells.

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IGSF3 mutation identified in patient with severe COPD alters cell function and motility

Cited by 5 publications

References 41 publications

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

IGSF3 is a homophilic cell adhesion molecule that drives lung metastasis of melanoma by promoting adhesion to vascular endothelium

IGSF3 is a homophilic cell adhesion molecule that drives lung metastasis of melanoma by promoting adhesion to vascular endothelium

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