The role of CD98hc in mouse macrophage functions

Tsumura, Hideki; Ito, Morihiro; Li, Xiaokang; Nakamura, Akinori; Ohnami, Naoko; Fujimoto, Junichiro; Komada, Hiroshi; Ito, Yasuhiko

doi:10.1016/j.cellimm.2012.04.012

Cited by 13 publications

(17 citation statements)

References 21 publications

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“…However, our present results suggest that targeted downregulation of CD98 expression in both epithelial cells and MPs could protect the intestinal barrier function and reduce MP activation. 10,[43][44][45] We herein demonstrate that we can deliver effective (yet low) doses of CD98 siRNA to mouse colonic epithelial cells and intestinal MPs via multiple oral administrations of encapsulated CD98 siRNA/PEI-loaded NPs. We found that the in vivo dose of encapsulated CD98 siRNA required to mediate gene silencing is 60 μg siRNA per kg, which is a respectively 10 to 40 times greater potency than previously reported in studies on local delivery in brain by microinfusion 46 or on systemic delivery by intravenous injection.…”

Section: Discussionmentioning

confidence: 78%

“…5,6 Our studies and other groups have shown that proinflammatory cytokines can upregulate CD98 expression in intestinal epithelial cells (IECs), [7][8][9] and CD98 is highly expressed in epithelial and immune cells (e.g., macrophages (MPs)) of the intestine. 10 Furthermore, increased CD98 expression has been found in colonic tissues from mice with active colitis 11 and in colonic biopsies from patients with Crohn's disease. 9 As CD98 expression plays crucial roles in controlling homeostatic and innate immune responses in the gut, the modulation of CD98 expression in colonic cells (epithelial and nonepithelial cells) could be a promising strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Intestinal Inflammation With CD98 siRNA/PEI–loaded Nanoparticles

et al. 2014

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Intestinal CD98 expression plays a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in intestinal cells therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as inflammatory bowel disease. Here, the advantages of nanoparticles (NPs) are used, including their ability to easily pass through physiological barriers and evade phagocytosis, high loading concentration, rapid kinetics of mixing and resistance to degradation. Using physical chemistry characterizations techniques, CD98 siRNA/polyethyleneimine (PEI)-loaded NPs was characterized (diameter of ~480 nm and a zeta potential of -5.26 mV). Interestingly, CD98 siRNA can be electrostatically complexed by PEI and thus protected from RNase. In addition, CD98 siRNA/PEI-loaded NPs are nontoxic and biocompatible with intestinal cells. Oral administration of CD98/PEI-loaded NPs encapsulated in a hydrogel reduced CD98 expression in mouse colonic tissues and decreased dextran sodium sulfate-induced colitis in a mouse model. Finally, flow cytometry showed that CD98 was effectively downregulated in the intestinal epithelial cells and intestinal macrophages of treated mice. Finally, the results collectively demonstrated the therapeutic effect of "hierarchical nano-micro particles" with colon-homing capabilities and the ability to directly release "molecularly specific" CD98 siRNA in colonic cells, thereby decreasing colitis.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Targeting Intestinal Inflammation With CD98 siRNA/PEI–loaded Nanoparticles

et al. 2014

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“…Likewise, other immune cells, such as macrophages, also require essential amino acids to mediate inflammation[61]. As tumor cells consume or release enzymes that degrade amino acids, the accessibility of amino acids to support T cell and macrophage effector functions can become limiting and waste products can accumulate.…”

Section: Tryptophan Metabolism In T Cell Mediated Inflammation and Camentioning

confidence: 99%

T cell metabolic fitness in antitumor immunity

Siska

Rathmell

2015

Trends in Immunology

252

219

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SUMMARY T cell metabolism plays a central role to support and shape immune responses and may play a key role in anti-tumor immunity. T cell metabolism is normally held under tight regulation in an immune response of glycolysis to promote effector T cell expansion and function. However, tumors may deplete nutrients, generate toxic products, or stimulate conserved negative feedback mechanisms, such as through PD-1, to impair effector T cell nutrient uptake and metabolic fitness. In addition, regulatory T cells are favored in low glucose conditions and may inhibit anti-tumor immune responses. Here we review how the tumor microenvironment modifies metabolic and functional pathways in T cells and how these changes may uncover new targets and challenges for cancer immunotherapy and treatment.

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“…In order to narrow down the role of CD98hc on B cells in EAE, I tested the competence of CD98-null B cells in these tasks. CD98hc was recently reported necessary for macrophage phagocytosis and antigen-presentation (Tsumura et al, 2012). I thus tested whether CD98-null B cells could phagocytose, process, and present antigen to CD4 T cells using OT-2 T cell receptor transgenic T cells (Barnden et al, 1998), which respond to a class-II MHC immunodominant peptide from ovalbumin (OVA 323-339 ).…”

Section: Resultsmentioning

confidence: 99%

CD98 is a potential target for ablating B cell clonal expansion and autoantibody in multiple sclerosis

Cantor

2014

Journal of Neuroimmunology

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Current B cell-directed therapies for multiple sclerosis impact multiple B cell functions. CD98hc enables B cell clonal expansion and antibody production. I probed the relative importance of autoantibody secretion vs. other B cell functions in MS and targeted CD98hc as a possible therapeutic strategy. I report that loss of CD98hc function in B cells largely prevents autoantibody production while preserving antigen-presenting and T cell-directing capacities. Mice lacking CD98hc in B cells are protected from EAE; importantly this is overcome with autoantibody-containing plasma. Thus CD98hc blockade is a possible avenue to treat MS by inhibiting clonal expansion and autoantibody.

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The role of CD98hc in mouse macrophage functions

Cited by 13 publications

References 21 publications

Targeting Intestinal Inflammation With CD98 siRNA/PEI–loaded Nanoparticles

Targeting Intestinal Inflammation With CD98 siRNA/PEI–loaded Nanoparticles

T cell metabolic fitness in antitumor immunity

CD98 is a potential target for ablating B cell clonal expansion and autoantibody in multiple sclerosis

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