Fibrin-mediated Protection Against Infection-stimulated Immunopathology

Johnson, Lawrence L.; Berggren, Kiera N.; Szaba, Frank M.; Chen, Wangxue; Smiley, Stephen T.

doi:10.1084/jem.20021493

Cited by 83 publications

(128 citation statements)

References 27 publications

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“…In addition to its role in hemostasis, the blood clotting system plays an important role in host defense against pathogens by stimulating inflammation, fibrin deposition, and possibly other mechanisms (19)(20)(21)(22). In addition, the contact pathway of blood clotting, although dispensable for normal hemostasis, appears to play important roles in kinin generation and host-pathogen interactions (23).…”

Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

495

623

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Inorganic polyphosphate is an abundant component of acidocalcisomes of bacteria and unicellular eukaryotes. Human platelet dense granules strongly resemble acidocalcisomes, and we recently showed that they contain substantial amounts of polyphosphate, which is secreted upon platelet activation. We now report that polyphosphate is a potent hemostatic regulator, accelerating blood clotting by activating the contact pathway and promoting the activation of factor V, which in turn results in abrogation of the function of the natural anticoagulant protein, tissue factor pathway inhibitor. Polyphosphate was also found to delay clot lysis by enhancing a natural antifibrinolytic agent, thrombin-activatable fibrinolysis inhibitor. Polyphosphate is unstable in blood or plasma, owing to the presence of phosphatases. We propose that polyphosphate released from platelets or microorganisms initially promotes clot formation and stability; subsequent degradation of polyphosphate by blood phosphatases fosters inhibition of clotting and activation of fibrinolysis during wound healing.factor V ͉ platelets ͉ tissue factor pathway inhibitor ͉ acidocalcisomes ͉ dense granules P olyphosphate (polyP) is widely distributed in biology, being found in bacteria, fungi, plants, and animals (1). The biologic functions of polyP have been studied most extensively in prokaryotes and unicellular eukaryotes, in which high levels of polyP accumulate in acidic organelles known as acidocalcisomes. PolyP in these organisms can reach chain lengths of several hundred phosphate units. In unicellular organisms, polyP has been shown to play essential roles in stress responses and virulence (1, 2), although its function in higher eukaryotes, including man, has not been extensively investigated. Recently, we reported that dense granules of human platelets strongly resemble acidocalcisomes and contain millimolar levels of polyP (with chain lengths of Ϸ70-75 phosphate units), making acidocalcisomes the only known class of organelle conserved during evolution from bacteria to humans (3). Human platelets each have three to eight dense granules (also called ␦ granules), a type of secretory granule that contains serotonin, ADP, ATP, and PP i in addition to polyP. Patients with dense granule defects exhibit bleeding diatheses, underscoring the role of these secretory granules in hemostasis (4). Platelets contain Ϸ0.74 nmol polyP per 10 8 platelets, which is secreted after stimulation by platelet agonists such as thrombin (3). Therefore, released polyP could readily attain a concentration of 3 M in whole blood, and this could be far higher in platelet-rich thrombi. (Concentrations of polyP are expressed in this paper as phosphate monomer.)The importance of platelets in hemostasis suggested to us that polyP may play an important role in the blood clotting system. In this study, we found that polyP of the size released from activated platelets has a strongly net procoagulant effect, which is exerted at several levels in the clotting͞fibrinolysis system: PolyP activate...

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Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

495

623

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“…cDNA encompassing the entire coding region of murine Fgl2 was cloned by PCR, sequenced, and used to reprobe previously described Northern blots (10,11). Real-time PCR-based quantitation of Fgl2 mRNA was performed and normalized to levels of ␤-2-microglobulin, as described (12). The Fgl2 primers (GGTCAACAGTTTGGAT-GGCAA, TTGAACCGGCTGTGACTGC) and probe (TTC-CAAGTGTCCCAGCCAAGAACACA) span an intron and do not amplify genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

“…Fibrin levels within tissue samples were measured quantitatively by Western blotting or qualitatively by immunohistochemistry, as described (12,14). Hematocrits and platelet counts were determined using a Coulter Counter (Beckman Coulter).…”

Section: Methodsmentioning

confidence: 99%

Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFNγ-inducible fibrinogen-like protein 2

Hancock

Szaba

Berggren

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Fibrinogen-like protein 2 (Fgl2, fibroleukin) is a leukocyte product that exhibits significant homology to secreted proteins of diverse function, including growth factors, lectins, and components of extracellular matrix. Prior studies found that Fgl2 is IFN␥-inducible, possesses direct coagulant activity, and inhibits T cell proliferation and dendritic cell maturation in vitro. Here, we demonstrate that Fgl2 expression is up-regulated during type 1 immunity in vivo and establish that such up-regulation is IFN␥-, signal transducer and activation of transcription protein 1-, and IFN response factor 1-dependent. To investigate functional roles for Fgl2 during type 1 immunity, we generated Fgl2-deficient mice. Those animals are born at predicted Mendelian frequencies, appear overtly healthy, and contain normal numbers and frequencies of lymphoid cells. Although Fgl2 is IFN␥-inducible and putatively regulates T cell activation͞proliferation, we demonstrate that Fgl2-deficient and control mice exhibit similar degrees of T cell expansion, immunopathology, and͞or pathogen burdens during protozoan (Toxoplasma gondii), bacterial (Yersinia enterocolitica, Listeria monocytogenes, and Mycobacterium tuberculosis), and viral (murine ␥-herpesvirus-68 and Sendai) infections. Fgl2-deficient mice also reject allografts with similar kinetics as control mice. Moreover, despite prior reports that Fgl2 functions as a procoagulant enzyme, we demonstrate that Fgl2-deficient and control mice produce similar levels of fibrin, a product of the coagulation cascade, during T. gondii infection and allograft rejection. Together, our findings suggest that Fgl2, although highly conserved and IFN␥-inducible, is not a critical mediator of either type 1 immunity or immuneassociated coagulant activity.

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“…with 300 50% egg infectious doses of the A/HK-x31 (x31, H3N2) (22) influenza A virus in 30 l of PBS. The T. gondii strain ME49 was obtained from brains of chronically infected mice, and infections were initiated by oral gavage of 10 cysts in 0.1 ml of diluted brain suspension (23). All experimental procedures involving mice were approved by the institutional animal care and use committee at Trudeau Institute.…”

Section: Mice and Viral Infectionsmentioning

confidence: 99%

“…Quantitative realtime RT-PCR was performed using gene-specific primers and probes (23) and the ABI PRISM 7700 Sequence BioDetector (Applied Biosystems) according to the manufacturer's instructions (TaqMan; PerkinElmer). Threshold cycle values for GAPDH were routinely between 15 and 18 cycles, and normalization to ␤ 2 -microglobulin gave similar results.…”

Section: Cytokine and Chemokine Quantificationmentioning

confidence: 99%

The Functional Heterogeneity of Type 1 Effector T Cells in Response to Infection Is Related to the Potential for IFN-γ Production

Mayer

Mohrs

Crowe

et al. 2005

The Journal of Immunology

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The expression of IFN-γ is a hallmark of Th1 cells and CD8+ effector T cells and is the signature cytokine of type 1 responses. However, it is not known whether T cells are homogeneous in their capacity to produce IFN-γ, whether this potential varies between tissues, and how it relates to the production of other effector molecules. In the present study we used bicistronic IFN-γ-enhanced yellow fluorescent protein (IFN-γ-eYFP) reporter mice (Yeti) and MHC class I tetramers to directly quantify IFN-γ expression at the single cell level. The eYFP fluorescence of Th1 cells and CD8+ effector T cells was broadly heterogeneous even before cell division and correlated with both the abundance of IFN-γ transcripts and the secretion of IFN-γ upon stimulation. CD4+ and CD8+ T cells of influenza-infected mice revealed a similarly heterogeneous IFN-γ expression, and eYFPhigh cells were only found in the infected lung. Ag-specific T cells were in all examined tissues eYFP+, but also heterogeneous in their reporter fluorescence, and eYFPhigh cells were also restricted to the infected lung. A similar heterogeneity was observed in Toxoplasma gondii-infected animals, but eYFPhigh cells were restricted to different tissues. Highly eYFP fluorescent cells produced elevated levels of proinflammatory cytokines and chemokines in addition to IFN-γ, suggesting their coregulated expression as a functional unit in highly differentiated effector T cells.

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Fibrin-mediated Protection Against Infection-stimulated Immunopathology

Cited by 83 publications

References 27 publications

Polyphosphate modulates blood coagulation and fibrinolysis

Polyphosphate modulates blood coagulation and fibrinolysis

Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFNγ-inducible fibrinogen-like protein 2

The Functional Heterogeneity of Type 1 Effector T Cells in Response to Infection Is Related to the Potential for IFN-γ Production

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