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The regulatory role of TRAF3 in myeloid cell-mediated control of chronic inflammation and tumor immunity
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Zhu, Sining. The regulatory role of TRAF3 in myeloid cell-mediated control of chronic inflammation and tumor immunity. Retrieved from https://doi.org/doi:10.7282/t3-cxr1-hg72

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TitleThe regulatory role of TRAF3 in myeloid cell-mediated control of chronic inflammation and tumor immunity
NameZhu, Sining (author); Xie, Ping (chair); Lattime, Edmund (internal member); Zhou, Renping (internal member); Covey, Lori (outside member); Rutgers University; School of Graduate Studies
Date Created2021
Other Date2021-05 (degree)
SubjectPharmacology, Cellular and Molecular
Extent1 online resource (xi, 153 pages)
DescriptionTumor necrosis factor receptor-associated factor 3 (TRAF3) is a cytoplasmic adaptor protein and a signal transducer of a variety of immune receptors involved in both adaptive and innate immunity. Previous study on myeloid cell-specific Traf3-deficient (M-Traf3-/-) mice revealed that aging M-Traf3-/- mice spontaneously develop chronic inflammation and tumors accompanied by striking expansion of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells with remarkable ability to suppress both innate and adaptive immune responses. To further investigate the role of myeloid cell TRAF3 in regulating MDSC expansion, we utilized an inflammation model by repeated injections of heat-killed Bacillus Calmette-Guérin (BCG), which closely resembles chronic inflammation and induces MDSC hyperexpansion in the spleen of young M-Traf3-/- mice. Using a new tumor transplantation model, we showed that in the presence of heat-killed BCG-induced chronic inflammation, young adult M-Traf3-/- mice with MDSC hyperexpansion failed to control B lymphoma growth and metastasis, which was associated with altered phenotypes of CD8, CD4 T cells and NK cells. Our results from mixed bone marrow (BM) chimera experiments demonstrated that TRAF3 inhibited MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. Cytokine array analysis and in vivo neutralization experiments identified G-CSF as the major extrinsic driver of MDSC expansion in M-Traf3-/- mice. Our detailed mechanistic investigation revealed that elevated levels of G-CSF in M-Traf3-/- mice were mainly contributed by a novel CCL22- CCR4-G-CSF axis acting in Traf3-/- inflammatory monocytes and macrophages. Furthermore, we investigated the cell-intrinsic mechanism underlying TRAF3-mediated regulation of MDSC expansion and elucidated a novel GM-CSF-TRAF3-STAT3 signaling axis that controls the proliferation of MDSCs. Overall, our findings uncover novel mechanistic insights on how myeloid cell TRAF3 restrains MDSC expansion, thereby preventing overzealous inflammation and indirectly promoting tumor immunity. Findings from this study will bring a new perspective for the design of novel MDSC-targeted therapeutic approaches for the treatment of chronic inflammation and cancers.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-cxr1-hg72
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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