Role of GCN2-dependent metabolic stress in regulating myeloid cell activation and differentiation.

Hdl Handle:
http://hdl.handle.net/10675.2/346287
Title:
Role of GCN2-dependent metabolic stress in regulating myeloid cell activation and differentiation.
Authors:
Liu, Haiyun
Abstract:
Amino acid metabolism is a pivotal regulator of innate and adaptive immunity. During inflammation, myeloid cells expressing enzymes such as indoleamine 2, 3-dioxygenase (IDO) and arginase 1 (ARG1) that degrade the amino acids L-tryptophan (L-Trp) and L-arginine (L-Arg), respectively. This serves a critical role in controlling cellular survival, development, and function. Therefore, it is important to understand the metabolic stress sensing pathways that regulate immune cell behavior, which further control the overall inflammatory environment. General Control Non-depressible 2 (GCN2) is an integrated stress response (ISR) kinase activated by intracellular amino acid limitation. Activated GCN2 phosphorylates eukaryotic initiation factor 2 α (eIF2α), which leads to global translation repression while up-regulating various stress-associated transcription factors. We found that in a murine LPS-induced endotoxemia model, IDO expression in macrophages depleted L-Trp that activated the GCN2. GCN2 signaling promoted macrophage cytokine production (IL-6, IL-12), increased CHOP expression and NF-κB activation. GCN2 knockout (GCN2KO) mice showed significantly lower serum and splenic cytokine levels compared to wild-type (WT) mice, and were protected from septicemia induced mortality. In the murine EG7 tumor model, GCN2 signaling was also activated in myeloid-derived suppressor cells (MDSCs) mediated by ARG1 depletion of L-Arg. We found that GCN2 was required for transcription factor C/EBPβ induction and monocytic bone marrow MDSC (BM-MDSC) development. GCN2KO BM-MDSCs showed significantly reduced ARG1 activity and failed to suppress antigen-specific cytotoxic T lymphocytes (CTLs) in vitro and in vivo. GCN2KO mice also exhibited increased efficacy in eliminating tumor cells after adoptive CTL transfer therapy. These data suggest that myeloid cells actively deplete intracellular amino acids to regulate their own cellular behavior. Different amino acid metabolic stress signals converge on the GCN2 pathway which serves as a secondary messenger to modulate downstream transcription factors. Depending on the type of inflammation, GCN2 can either promote pro-inflammatory responses or the immunosuppressive function of myeloid cells. Thus, targeting the GCN2 pathway in myeloid cells may have great potential in clinical therapy.
Affiliation:
Department of Medicine
Issue Date:
Dec-2014
URI:
http://hdl.handle.net/10675.2/346287
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1651550215?accountid=12365
Type:
Dissertation
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorLiu, Haiyunen
dc.date.accessioned2015-03-06T16:13:56Zen
dc.date.available2015-03-06T16:13:56Zen
dc.date.issued2014-12en
dc.identifier.urihttp://hdl.handle.net/10675.2/346287en
dc.description.abstractAmino acid metabolism is a pivotal regulator of innate and adaptive immunity. During inflammation, myeloid cells expressing enzymes such as indoleamine 2, 3-dioxygenase (IDO) and arginase 1 (ARG1) that degrade the amino acids L-tryptophan (L-Trp) and L-arginine (L-Arg), respectively. This serves a critical role in controlling cellular survival, development, and function. Therefore, it is important to understand the metabolic stress sensing pathways that regulate immune cell behavior, which further control the overall inflammatory environment. General Control Non-depressible 2 (GCN2) is an integrated stress response (ISR) kinase activated by intracellular amino acid limitation. Activated GCN2 phosphorylates eukaryotic initiation factor 2 α (eIF2α), which leads to global translation repression while up-regulating various stress-associated transcription factors. We found that in a murine LPS-induced endotoxemia model, IDO expression in macrophages depleted L-Trp that activated the GCN2. GCN2 signaling promoted macrophage cytokine production (IL-6, IL-12), increased CHOP expression and NF-κB activation. GCN2 knockout (GCN2KO) mice showed significantly lower serum and splenic cytokine levels compared to wild-type (WT) mice, and were protected from septicemia induced mortality. In the murine EG7 tumor model, GCN2 signaling was also activated in myeloid-derived suppressor cells (MDSCs) mediated by ARG1 depletion of L-Arg. We found that GCN2 was required for transcription factor C/EBPβ induction and monocytic bone marrow MDSC (BM-MDSC) development. GCN2KO BM-MDSCs showed significantly reduced ARG1 activity and failed to suppress antigen-specific cytotoxic T lymphocytes (CTLs) in vitro and in vivo. GCN2KO mice also exhibited increased efficacy in eliminating tumor cells after adoptive CTL transfer therapy. These data suggest that myeloid cells actively deplete intracellular amino acids to regulate their own cellular behavior. Different amino acid metabolic stress signals converge on the GCN2 pathway which serves as a secondary messenger to modulate downstream transcription factors. Depending on the type of inflammation, GCN2 can either promote pro-inflammatory responses or the immunosuppressive function of myeloid cells. Thus, targeting the GCN2 pathway in myeloid cells may have great potential in clinical therapy.en
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1651550215?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectAmino Acidsen
dc.subjectmetabolic stressen
dc.subjectGCN2en
dc.subjectmyeloid cellsen
dc.subjectindoleamine 2,3 dioxygenaseen
dc.subjectIDOen
dc.subjectArginase-1en
dc.subjectARG1en
dc.titleRole of GCN2-dependent metabolic stress in regulating myeloid cell activation and differentiation.en
dc.typeDissertationen
dc.contributor.departmentDepartment of Medicineen
dc.description.advisorMcGaha, Tracyen
dc.description.committeeMunn, David; Huang, Lei; Johnson, Theodore; Horuzsko, Anatolijen
dc.description.degreeDoctor of Philosophy (Ph.D.)en
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