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AMP-activated protein kinase alpha1 promotes tumor development via FOXP3 elevation in tumor-infiltrating Treg cells.

ABSTRACT: Overwhelming evidence indicates that infiltration of tumors by Treg cells with elevated levels of FOXP3 suppresses the host antitumor immune response. However, the molecular mechanisms that maintain high expression of FOXP3 in tumor-infiltrating Treg cells remain elusive. Here, we report that AMP-activated protein kinase alpha1 (AMPKα1) enables high FOXP3 expression in tumor-infiltrating Treg cells. Mice with Treg-specific AMPKα1 deletion showed delayed tumor progression and enhanced antitumor T cell immunity. Further experiments showed that AMPKα1 maintains the functional integrity of Treg cells and prevents interferon-γ production in tumor-infiltrating Treg cells. Mechanistically, AMPKα1 maintains the protein stability of FOXP3 in Treg cells by downregulating the expression of E3 ligase CHIP (STUB1). Our results suggest that AMPKα1 activation promotes tumor growth by maintaining FOXP3 stability in tumor-infiltrating Treg cells and that selective inhibition of AMPK in Treg cells might be an effective anti-tumor therapy.

SUBMITTER: An J

PROVIDER: S-EPMC8704466 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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AMP-activated protein kinase alpha1 promotes tumor development via FOXP3 elevation in tumor-infiltrating Treg cells.

An Junqing J Ding Ye Y Yu Changjiang C Li Jian J You Shaojin S Liu Zhixue Z Song Ping P Zou Ming-Hui MH

iScience 20211204 1

Overwhelming evidence indicates that infiltration of tumors by Treg cells with elevated levels of FOXP3 suppresses the host antitumor immune response. However, the molecular mechanisms that maintain high expression of FOXP3 in tumor-infiltrating Treg cells remain elusive. Here, we report that AMP-activated protein kinase alpha1 (AMPKα1) enables high FOXP3 expression in tumor-infiltrating Treg cells. Mice with Treg-specific AMPKα1 deletion showed delayed tumor progression and enhanced antitumor T ...[more]

PMID: 34988407

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Project description:Background & aimsGlycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.MethodsWe created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.ResultsCompared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients.ConclusionsGsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.Lay summaryGlycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.

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AMP-activated protein kinase alpha1 promotes tumor development via FOXP3 elevation in tumor-infiltrating Treg cells.

Publications

AMP-activated protein kinase alpha1 promotes tumor development via FOXP3 elevation in tumor-infiltrating Treg cells.

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