IDO1 Signaling through GCN2 in a Subpopulation of Gr-1+ Cells Shifts the IFNγ/IL6 Balance to Promote Neovascularization.
Cancer Immunol Res
; 9(5): 514-528, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33622713
ABSTRACT
In addition to immunosuppression, it is generally accepted that myeloid-derived suppressor cells (MDSC) also support tumor angiogenesis. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) has been implicated in promoting neovascularization through its positioning as a key regulatory node between the inflammatory cytokines IFNγ and IL6. Here, we report that within the heterogeneous expanse of Gr-1+ MDSCs, both IDO1 expression and the ability to elicit neovascularization in vivo were associated with a minor subset of autofluorescent, CD11blo cells. IDO1 expression was further restricted to a discrete, CD11c and asialo-GM1 double-positive subpopulation of these cells, designated here as IDVCs (IDO1-dependent vascularizing cells), due to the dominant role that IDO1 activity in these cells was found to play in promoting neovascularization. Mechanistically, the induction of IDO1 in IDVCs provided a negative-feedback constraint on the antiangiogenic effect of host IFNγ by intrinsically signaling for the production of IL6 through general control nonderepressible 2 (GCN2)-mediated activation of the integrated stress response. These findings reveal fundamental molecular and cellular insights into how IDO1 interfaces with the inflammatory milieu to promote neovascularization.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Interleucina-6
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Interferon gama
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Proteínas Serina-Treonina Quinases
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Indolamina-Pirrol 2,3,-Dioxigenase
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Inflamação
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Neovascularização Patológica
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article