Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model

Liu, Jinfeng; Xiao, Siyu; Huang, Shiguang; Pei, Fuquan; Lü, Fangli

doi:10.1007/s00436-015-4775-6

Cited by 15 publications

(12 citation statements)

References 30 publications

(26 reference statements)

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“…However, studies in Mtb point out that the Tim-3 expression and T cell function may be pathogen-specific. Consistent with this, in murine malaria, expression of both Tim-3 and Galectin-9 were associated with liver damage and acute lung injury ( 128 , 129 ), suggesting a role in pathogenesis. It would be of interest to study if Tim-3 signaling has any role in prophylactic parasite vaccines.…”

Section: Tim-3supporting

confidence: 65%

Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Gannavaram¹,

Bhattacharya²,

Ismail³

et al. 2016

Front. Immunol.

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No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4+ and CD8+ T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the polarization of antigen-presenting cells and subsequent role of costimulatory and coinhibitory molecules in mediating vaccine-induced immunity using live-attenuated Leishmania parasites as specific examples.

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Section: Tim-3supporting

confidence: 65%

Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Gannavaram¹,

Bhattacharya²,

Ismail³

et al. 2016

Front. Immunol.

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“…Similarly, Tim-3 is expressed on a variety of immune cells, such as T cells, monocytes, macrophages, and DCs, and regulates the innate immune response39. Previous works from our laboratory have shown the upregulation of Tim-3 and Gal-9 in Pb ANKA-induced ALI in the mouse model40. In the current study, we further demonstrated that Gal-9 and Tim-3 were expressed mainly on infiltrating mononuclear cells in the lung tissues after Pb ANKA infection.…”

Section: Discussionmentioning

confidence: 98%

Blockage of Galectin-receptor Interactions by α-lactose Exacerbates Plasmodium berghei-induced Pulmonary Immunopathology

Liu

Huang

et al. 2016

Sci Rep

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Malaria-associated acute lung injury (ALI) is a frequent complication of severe malaria that is often caused by “excessive” immune responses. To better understand the mechanism of ALI in malaria infection, here we investigated the roles of galectin (Gal)-1, 3, 8, 9 and the receptors of Gal-9 (Tim-3, CD44, CD137, and PDI) in malaria-induced ALI. We injected alpha (α)-lactose into mice-infected with Plasmodium berghei ANKA (PbANKA) to block galectins and found significantly elevated total proteins in bronchoalveolar lavage fluid, higher parasitemia and tissue parasite burden, and increased numbers of CD68+ alveolar macrophages as well as apoptotic cells in the lungs after blockage. Additionally, mRNA levels of Gal-9, Tim-3, CD44, CD137, and PDI were significantly increased in the lungs at day 5 after infection, and the levels of CD137, IFN-α, IFN-β, IFN-γ, IL-4, and IL-10 in the lungs were also increased after α-lactose treatment. Similarly, the levels of Gal-9, Tim-3, IFN-α, IFN-β, IFN-γ, and IL-10 were all significantly increased in murine peritoneal macrophages co-cultured with PbANKA-infected red blood cells in vitro; but only IFN-α and IFN-β were significantly increased after α-lactose treatment. Our data indicate that Gal-9 interaction with its multiple receptors play an important role in murine malaria-associated ALI.

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“…This study revealed the presence of Gal-9 in plasma in malaria patients and showed that plasma levels of Gal-9 accurately reflect the status of inflammation and recovery during malaria infection for the first time though the tissue expression of Gal-9 and Tim-3 was demonstrated in murine malaria model [ 21 , 22 ]. The elevation of Gal-9 was reported in other acute and non-acute infectious diseases such as dengue virus infection (median level was 1525 pg/mL), leptospirosis (616 pg/mL) [ 9 ], acute HIV infection (~2300 pg/mL) [ 8 ] and active tuberculosis (200 pg/mL) [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…Beside immune modulatory activities, Gal-9 is released from infected or damaged cells, and could act as danger signal molecules [ 9 ], by initiating inflammation as reported in murine respiratory tularaemia [ 38 ]. Moreover the Tim-3-Gal-9 expression was found to be elevated in acute lung injury in a murine malarial model [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…These emerging regulatory activities of Gal-9 involving co-inhibitory receptors took us to investigate Gal-9 in malaria, though how Tim-3 functions to determine effector T cell responses is not yet well clarified [ 15 ]. Recently expression of Gal-9 and Tim-3 was demonstrated in lung, mediastinal lymph nodes and liver tissues in murine malaria model [ 22 , 23 ]; however, the plasma levels of Gal-9 in human malaria patients has not been evaluated yet.…”

Section: Introductionmentioning

confidence: 99%

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Plasma levels of Galectin-9 reflect disease severity in malaria infection

Dembele

Chagan-Yasutan

Niki

et al. 2016

Malar J

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BackgroundGalectin-9 (Gal-9) is a β-galactoside-binding lectin that interacts with sugar moieties on glycoproteins and glycolipids of cells and pathogens. Gal-9 is known as an immune modulator that induces cell death via interaction with T cell immunoglobulin and mucin domain-3 (Tim3), a co-inhibitory receptor, and it inhibits production of several pro-inflammatory cytokines (TNF, IL-6 and IL-1α) and enhances production of IL-10. To understand the immune pathology of malaria, the Gal-9 in plasma was measured.MethodsPlasma samples and clinical parameters were obtained from 50 acute malaria cases (nine severe and 41 uncomplicated cases) from Thailand at three time points: day 0, day 7 and day 28. Gal-9 levels were determined by ELISA. A total of 38 species of cytokines and chemokines were measured using a BioPlex assay.ResultsGal-9 levels were higher at day 0 compared to day 7 and day 28 (P < 0.0001). Gal-9 levels were also higher in severe malaria (SM) cases compared to uncomplicated (UM) cases at day 0 and day 7 (923 vs 617 pg/mL; P = 0.03, and 659 vs 348 pg/mL; P = 0.02 respectively). Median Gal-9 levels were higher in patients with blood urea nitrogen to creatinine ratio (BUN/creatinine) ≥20 (mg/dL) than in patients with BUN/creatinine <20 (mg/dL) at day 0 (817.3 vs 576.2 pg/mL, P = 0.007). Gal-9 was inversely significantly correlated with chloride levels in both SM and UM cases (rs = −0.73 and rs = −0.46, respectively). In both UM and SM cases, Gal-9 was significantly associated with pro- and anti-inflammatory cytokines and chemokines such as TNF, IL-6, IFN-α2, IFN-γ, IL-1Ra and IL-10. These correlations were observed at day 0 but disappeared at day 28.ConclusionsGal-9 is released during acute malaria, and reflects its severity. This elevation of Gal-9 in acute malaria infection raises the possibility of its role in termination of the immune response by binding to Tim-3, a receptor of Gal-9.

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Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model

Cited by 15 publications

References 30 publications

Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Blockage of Galectin-receptor Interactions by α-lactose Exacerbates Plasmodium berghei-induced Pulmonary Immunopathology

Plasma levels of Galectin-9 reflect disease severity in malaria infection

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