期刊
BLOOD
卷 138, 期 17, 页码 1554-1569出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020009594
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资金
- Erdheim-Chester Disease Global Alliance (ECDGA)
- Advanced Light and Electron Microscopy BioImaging Center (ALEMBIC)
- Italian Association for Cancer Research - AIRC [22136]
- FOREUM
- Interleukin Foundation
- Netherlands Organization for Scientific Research
- European Research Council
This study revealed the deleterious potential of inappropriate activation of trained immunity in the pathogenesis of human inflammatory myeloid neoplasms, and highlighted the opportunity for inhibition of trained immunity in conditions characterized by maladaptive myeloid-driven inflammation. Effective therapeutic strategies in patients with Erdheim-Chester disease combat the maladaptive trained immunity phenotype, and pharmacologic inhibition of immunometabolic changes underlying trained immunity effectively dampens cytokine production by myeloid cells.
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
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