CAT2 arginine transporter deficiency significantly reduces iNOS‐mediated NO production in astrocytes

Manner, Cathyryne K.; Nicholson, Benjamin; MacLeod, Carol L.

doi:10.1046/j.1471-4159.2003.01695.x

Cited by 46 publications

(31 citation statements)

References 39 publications

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“…In line with findings of other investigators (53,71,72), our studies showed that inhibition of NOS2 and of IFN-␥ signaling abrogated the suppressive effect of P. gingivalis-induced MDSC on CD4 ϩ T cell proliferation. These observations indirectly suggest that secretion of NO requires surface and soluble signals, such as NOS2 and IFN-␥ from activated T cells, factors that contribute to immune suppression.…”

Section: Discussionsupporting

confidence: 92%

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

Zhang

et al. 2017

Infect Immun

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Porphyromonas gingivalis, a major etiologic agent of periodontitis, has been reported to induce the expansion of myeloid-derived suppressor cells (MDSC); however, little is known regarding the subpopulations of MDSC expanded by P. gingivalis infection. Flow cytometry was used to evaluate bone marrow and spleen cells from mice infected with P. gingivalis and controls for surface expression of CD11b, Ly6G, and Ly6C. To characterize the phenotype of MDSC subpopulations induced by infection, cells were sorted based on the differential expression of Ly6G and Ly6C. Moreover, since MDSC are suppressors of T cell immune activity, we determined the effect of the induced subpopulations of MDSC on the proliferative response of OVAspecific CD4 ϩ T cells. Lastly, the plasticity of MDSC to differentiate into osteoclasts was assessed by staining for tartrate-resistant acid phosphatase activity. P. gingivalis infection induced the expansion of three subpopulations of MDSC (Ly6G ϩϩ Ly6C ϩ , Ly6G ϩ Ly6C ϩϩ , and Ly6G ϩ Ly6C ϩ ); however, only CD11b ϩ Ly6G ϩ Ly6C ϩϩ -exp ressing cells exerted a significant suppressive effect on T cell proliferation. Inhibition of proliferative responses required T cell-MDSC contact and was mediated by inducible nitric oxide synthase and cationic amino acid transporter 2 via gamma interferon. Furthermore, only the CD11b ϩ Ly6G ϩ Ly6C ϩϩ subpopulation of MDSC induced by P. gingivalis infection was able to differentiate into osteoclasts. Thus, the inflammatory response induced by P. gingivalis infection promotes the expansion of immune-suppressive cells and consequently the development of regulatory inhibitors that curtail the host response. Moreover, monocytic MDSC have the plasticity to differentiate into OC, thus perhaps contributing to the OC pool in states of periodontal disease. KEYWORDS periodontitis, Porphyromonas gingivalis, MDSC Periodontitis is an infectious inflammatory process that affects the periodontium. The continuous inflammation characteristic of this disease underlies its chronic inflammatory nature, ultimately destroying the supportive tissues of teeth (1, 2). Current thought suggests that the development of periodontitis is associated with a shift from a balanced microbial community to an imbalanced one, with the ability to undermine the host response and allowing the persistence of pathogens in the inflammatory milieu (3,4). Within the oral microflora, Porphyromonas gingivalis is considered a key pathogen able to exert an influence on the microbial environment and, consequently, in concert with other periodontal microorganisms, initiate and promote periodontitis (5, 6). P. gingivalis has a number of virulence factors by which it can escape or dampen host immunity, alter cytokine production, and affect the cell signaling mechanisms (7-10). Interestingly, studies in mice infected with P. gingivalis

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Section: Discussionsupporting

confidence: 92%

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

Zhang

et al. 2017

Infect Immun

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“…1, A and B). These results showed that the release of NO was significantly reduced in either peritoneal or airway macrophages in the absence of the CAT-2 gene, as is consistent with what has been previously reported (26).…”

Section: Resultssupporting

confidence: 93%

CAT-2 amplifies the agonist-evoked force of airway smooth muscle by enhancing spermine-mediated phosphatidylinositol-(4)-phosphate-5-kinase-γ activity

Chen

MacLeod²,

Deng³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…However, the background of KO animals (C57BL/6 or BALB/c) does not explain these discrepancies because similar results were found when we used the two strains (data not shown). It should be noted that for these authors, the production of NO in fibroblasts and astrocytes is not completely dependent on CAT2 (35,36).…”

Section: Discussionmentioning

confidence: 79%

Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages

Yeramian

Martín

Serrat

et al. 2006

The Journal of Immunology

121

110

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Arginine is processed by macrophages in response to the cytokines to which these cells are exposed. Th1-type cytokines induce NO synthase 2, which metabolizes arginine into nitrites, while the Th2-type cytokines produce arginase, which converts arginine into polyamines and proline. Activation of bone marrow-derived macrophages by these two types of cytokines increases l-arginine transport only through the y+ system. Analysis of the expression of the genes involved in this system showed that Slc7A1, encoding cationic amino acid transporters (CAT)1, is constitutively expressed and is not modified by activating agents, while Slc7A2, encoding CAT2, is induced during both classical and alternative activation. Macrophages from Slc7A2 knockout mice showed a decrease in l-arginine transport in response to the two kinds of cytokines. However, while NO synthase 2 and arginase expression were unmodified in these cells, the catabolism of arginine was impaired by both pathways, producing smaller amounts of nitrites and also of polyamines and proline. In addition, the induction of Slc7A2 expression was independent of the arginine available and of the enzymes that metabolize it. In conclusion, the increased arginine transport mediated by activators is strongly regulated by CAT2 expression, which could limit the function of macrophages.

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CAT2 arginine transporter deficiency significantly reduces iNOS‐mediated NO production in astrocytes

Cited by 46 publications

References 39 publications

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

CAT-2 amplifies the agonist-evoked force of airway smooth muscle by enhancing spermine-mediated phosphatidylinositol-(4)-phosphate-5-kinase-γ activity

Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages

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