Intracellular Galectin-9 Controls Dendritic Cell Function by Maintaining Plasma Membrane Rigidity

Cano, Laia Querol; Tagit, Oya; Dölen, Yusuf; Duffelen, Anne van; Dieltjes, Shannon; Buschow, Sonja I.; Niki, Toshiro; Hirashima, Mitsuomi; Joosten, Ben; Dries, Koen van den; Cambi, Alessandra; Figdor, Carl G.; Spriel, Annemiek B. van

doi:10.1016/j.isci.2019.11.019

Cited by 24 publications

(24 citation statements)

References 65 publications

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“…Therefore, our data suggest that the massive level of plasma Gal-9 in COVID-19 patients serves as a DAMP (34) that exerts its actions on several immune cells such as monocytes/macrophages, NK cells, and neutrophils to exacerbate cytokine storm. In agreement, we found induction of IL-6 and TNF-a by rhGal-9 in PBMCs, in particular, monocytes and NK cells, which is consistent with other reports (61,62). The concentration of Gal-9 needed to evoke these responses was far lower (2,000 pg/ml) than the highest concentration of Gal-9 observed in some patients (.100,000 pg/ml).…”

Section: Discussionsupporting

confidence: 93%

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Bozorgmehr

Mashhouri

Rosero

et al. 2021

mBio

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The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor β (TGF-β) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro. Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients. IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro. Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

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Section: Discussionsupporting

confidence: 93%

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Bozorgmehr

Mashhouri

Rosero

et al. 2021

mBio

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“…Cano et al identified the function of Gal-9 in actin cytoskeleton reorganization. They also described an interaction between Gal-9 and C-type lectin receptor within both the human and murine DC cytosol [ 35 ], which indicates that Gal-9 is an evolutionarily conserved lectin which functions in maintaining the cortical cytoskeleton structure and function of DCs. Furthermore, their study confirmed that intracellular Gal-9 is required for actin polymerization and controls plasma membrane rigidity by enhancing the activity of the actin-binding protein, RAS-related C3 botulinum toxin substrate 1 (Rac-1).…”

Section: Galectin-9 Molecular and Cellular Biologymentioning

confidence: 99%

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

et al. 2021

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Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.

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“…This may result, in part, from impaired DC activation, which is essential for disease onset in pristane-induced autoimmunity ( Richard and Gilkeson, 2018 ). In this case, intracellular Gal9 interacts with the cortical actin cytoskeleton to facilitate phagocytosis and DC activation ( Querol Cano et al, 2019 ), and therefore, genetic deletion of Gal9 may be detrimental for DC-dependent models of autoimmunity. The growing compendium of data suggest that Gal9 may have pleotropic effects that result in context-dependent and cell-type-specific regulation ( Panda and Das, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 regulates the threshold of B cell activation and autoimmunity

Smith

Fawaz

Treanor

2021

eLife

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Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.

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Intracellular Galectin-9 Controls Dendritic Cell Function by Maintaining Plasma Membrane Rigidity

Cited by 24 publications

References 65 publications

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases

Galectin-9 regulates the threshold of B cell activation and autoimmunity

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