Intracellular Galectin-9 controls dendritic cell function by maintaining plasma membrane rigidity

Cano, Querol; Tagit, Oya; Duffelen, Anne van; Dieltjes,; Buschow, Sonja I.; Niki, Toshiro; Hirashima,; Joosten,; Dries, van den N.; Cambi, Alessandra; Figdor, Carl G.; Spriel, van

doi:10.1101/739797

Cited by 4 publications

(9 citation statements)

References 69 publications

(73 reference statements)

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“…Illustrating its versatility, galectin-9 was first characterised as an eosinophil chemo-attractant 23 , it induces cell death and immune tolerance by binding T cell immunoglobulin-3 in T helper 1 (TH1) cells 24 , it promotes the expansion of immunosuppressive macrophages 25 and monocytic myeloid-derived suppressor cells 26 and it has been shown to negatively regulate B cell receptor signalling 27,28 . Contrary to these reports implicating an immunosuppressive role for galectin-9, we and others have previously identified galectin-9 to positively regulate DC biology although many of its functions in myeloid cells remain poorly defined [29][30][31] .…”

Section: Introductioncontrasting

confidence: 99%

“…However, the mechanism(s) by which galectin-9 mediates DC motility are not delineated. We have recently reported intracellular galectin-9 to be involved in regulating actin cytoskeleton reorganisation and stabilising the plasma membrane in DCs 30 . In addition, dengue virus-infected DCs were shown to up-regulate galectin-9 expression and their ability to migrate towards CCL19 and CXCL12 cytokines 36 .…”

Section: Introductionmentioning

confidence: 99%

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Galectin-9 regulates dendritic cell contractility and migration via RhoA

Franken,

Cuenca-Escalona,

Stehle

et al. 2023

Preprint

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To initiate adaptive immune responses, dendritic cells (DCs) migrate long distances to transport antigens from peripheral tissues to draining lymph nodes employing a so-called ameboid migration mode. Despite its critical importance, the specific molecular mechanisms that regulate DC migration are poorly characterised. Galectins, a family of β-galactoside-binding proteins, constitute a novel mechanism of membrane organisation at the cell surface and, in this way, exert crucial roles in multiple physiological and pathological processes. Nonetheless, the molecular mechanisms that underlie galectin functions are poorly described and their membrane interacting partners are mostly unknown.Here, we report that galectin-9 is required for the dynamic behaviour and motility of DCs. We demonstrate that galectin-9 deficiency results in impaired chemokine-driven and basal DC migration both in human and mouse, suggesting a conserved function for galectin-9. Deficiency in contractility was identified as the underlying mechanism, which could be rescued by restoring membrane-bound galectin-9 levels. Furthermore, we show that galectin-9 controls RhoA activity and downstream signalling, in turn causing rearrangements of the actin cytoskeleton at the cell rear that promote DC efficient migration. Galectin-9 interaction with the adhesion receptor CD44 was required for its function enhancing DC migration. Remarkably, analysis of DC motility in a 3D environment containing a tumour spheroid revealed galectin-9 is required for DC persistent migration towards the tumour and for DC infiltration. Moreover, exogenous galectin-9 rescued the motility of immunocompromised primary blood DCs, revealing a novel role for galectin-9 in the tumour microenvironment, with potential implications for DC-based immunotherapies.

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Section: Introductioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Galectin-9 regulates dendritic cell contractility and migration via RhoA

Franken,

Cuenca-Escalona,

Stehle

et al. 2023

Preprint

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“…LGALS9 promotes and stabilizes inducible regulatory T cells (iTregs) (39). In DCs, LGALS9 is important for pathogen uptake and is indispensable for phagocytosis (40). Treg responses in the natural reservoirs of viral hemorrhagic fevers (VHFs) have been observed previously, as the rodent reservoirs of hantaviruses avoid immunopathology by the upregulation of Tregs to actively counteract inflammatory responses (41,42).…”

Section: Discussionmentioning

confidence: 93%

Rousette Bat Dendritic Cells Overcome Marburg Virus-Mediated Antiviral Responses by Upregulation of Interferon-Related Genes While Downregulating Proinflammatory Disease Mediators

Prescott

Guito

Spengler

et al. 2019

mSphere

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Dysregulated and maladaptive immune responses are at the forefront of human diseases caused by infection with zoonotic viral hemorrhagic fever viruses. Elucidating mechanisms of how the natural animal reservoirs of these viruses coexist with these agents without overt disease, while permitting sufficient replication to allow for transmission and maintenance in a population, is important for understanding the viral ecology and spillover to humans. The Egyptian rousette bat (ERB) has been identified as a reservoir for Marburg virus (MARV), a filovirus and the etiological agent of the highly lethal Marburg virus disease. Little is known regarding how these bats immunologically respond to MARV infection. In humans, macrophages and dendritic cells (DCs) are primary targets of infection, and their dysregulation is thought to play a central role in filovirus diseases, by disturbing their normal functions as innate sensors and adaptive immune response facilitators while serving as amplification and dissemination agents for the virus. The infection status and responses to MARV in bat myeloid-lineage cells are uncharacterized and likely represent an important modulator of the bat’s immune response to MARV infection. Here, we generate DCs from the bone marrow of rousette bats. Infection with a bat isolate of MARV resulted in a low level of transcription in these cells and significantly downregulated DC maturation and adaptive immune-stimulatory pathways while simultaneously upregulating interferon-related pathogen-sensing pathways. This study provides a first insight into how the bat immune response is directed toward preventing aberrant inflammatory responses while mounting an antiviral response to defend against MARV infection. IMPORTANCE Marburg viruses (MARVs) cause severe human disease resulting from aberrant immune responses. Dendritic cells (DCs) are primary targets of infection and are dysregulated by MARV. Dysregulation of DCs facilitates MARV replication and virus dissemination and influences downstream immune responses that result in immunopathology. Egyptian rousette bats (ERBs) are natural reservoirs of MARV, and infection results in virus replication and shedding, with asymptomatic control of the virus within weeks. The mechanisms that bats employ to appropriately respond to infection while avoiding disease are unknown. Because DC infection and modulation are important early events in human disease, we measured the transcriptional responses of ERB DCs to MARV. The significance of this work is in identifying cell type-specific coevolved responses between ERBs and MARV, which gives insight into how bat reservoirs are able to harbor MARV and permit viral replication, allowing transmission and maintenance in the population while simultaneously preventing immunopathogenesis.

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“…Galectin-9 administration increased the number of Tim-3 + CD86 + mDCs and enhanced antitumor immunity [35]. Recently, intracellular galectin-9 was shown to be indispensable for plasma membrane integrity and structure in DCs and essential for C-type lectin receptor-mediated pathogen uptake by DCs [36]. In our study, high galectin-9 expression was positively correlated with a large amount of mDC infiltration and negatively correlated with imDC infiltration in CRC, and galectin-9 was involved in interferon-gamma, response to type I interferon, adaptive immune response, and antigen processing and presentation.…”

Section: Discussionmentioning

confidence: 99%

Galectin-9 expression clinically associated with mature dendritic cells infiltration and T cell immune response in colorectal cancer

et al. 2022

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Background Galectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study. Methods The expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases. Results The level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p < 0.0001). In the relationship between galectin-9 expression and the infiltration of DCs, there was a negative correlation in CD1a + immature DCs (R = -0.263, p = 0.042). A strong positive correlation was observed in CD208 + mature DCs (R = 0.391, p < 0.01). Patients with high galectin-9 expression also exhibited abundant CD8 + T-cell and CD3 + T-cell infiltration. Conclusion Collectively, our findings provide evidence that galectin-9 may increase the antitumor immune response of patients with CRC. DCs play an important role in galectin-9-mediated antitumor immune responses, which provides further insight into the development of immunotherapy.

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Intracellular Galectin-9 controls dendritic cell function by maintaining plasma membrane rigidity

Cited by 4 publications

References 69 publications

Galectin-9 regulates dendritic cell contractility and migration via RhoA

Galectin-9 regulates dendritic cell contractility and migration via RhoA

Rousette Bat Dendritic Cells Overcome Marburg Virus-Mediated Antiviral Responses by Upregulation of Interferon-Related Genes While Downregulating Proinflammatory Disease Mediators

Galectin-9 expression clinically associated with mature dendritic cells infiltration and T cell immune response in colorectal cancer

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