The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Tet2 restrains inflammatory gene expression in macrophages
Open accessAbstract
Tet methylcytosine dioxygenase 2 (TET2) is one of the earliest and most frequently mutated genes in clonal hematopoiesis of indeterminate potential (CHIP) and myeloid cancers, including myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). TET2 catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, leading to DNA demethylation, and also affects transcription by recruiting histone modifiers. Inactivating TET2 mutations cause epigenetic dysregulation, clonal hematopoietic stem cell (HSC) dominance, and monocytic lineage skewing. Here, we found that Tet2 was the most highly expressed Tet enzyme in murine macrophage (MΦ) differentiation. Tet2 transcription was further induced by lipopolysaccharide (LPS), but not interleukin (IL)-4, stimulation, potentially in a nuclear factor κβ-dependent manner. Tet2 loss did not affect early LPS gene responses in vitro, but increased Il-1b, Il-6, and Arginase 1 (Arg1) mRNA expression at later stages of stimulation in bone-marrow-derived MΦs (BMMΦs). Tet2-deficient peritoneal MΦs, however, demonstrated profound, constitutive expression of LPS-induced genes associated with an inflammatory state in vivo. In contrast, Tet2 deficiency did not affect alternative MΦ gene expression significantly in response to IL-4. These results suggested impaired resolution of inflammation in the absence of Tet2 both in vitro and in vivo. For the first time, we also detected TET2 mutations in BMMΦs from MDS and CMML patients and assayed their effects on LPS responses, including their potential influence on human IL-6 expression. Our results show that Tet2 restrains inflammation in murine MΦs and mice, raising the possibility that loss of TET2 function in MΦs may alter the immune environment in the large elderly population with TET2-mutant CHIP and in TET2-mutant myeloid cancer patients.
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In the citing paper
“A role for TET2 during the resolution of inflammation has also been described in bone-derived macrophages (Cull et al., 2017).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Cull et al., 2017
In the citing paper
“Since many CH-associated mutations themselves contribute to increased inflammatory signaling, including mutations in TET2, FLT3, JAK2, STAT1, CBL, and RAS (Azrakhsh et al., 2019; Cull et al., 2017; Jaiswal et al., 2017)”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Cull et al., 2017
In the citing paper
“in the context of CHIP, Tet2 loss-of-function mutations in myeloid cells result in increased proinflammatory responses, with reported increases in both IL-124,43 and IL-6 production,27”
From Aging drives Tet2 +/− clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [43]
In the citing paper
“also found that Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with low-density lipoprotein or endotoxin 79,86,92”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [92]
In the citing paper
“Subsequent studies have confirmed the over-expression of Il6”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [92]
Citations
Cites
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Mutation in TET2 in Myeloid Cancers
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Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
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Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation
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Cited by
Sorted by citations
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156
“Subsequent studies have confirmed the overexpression of Il6 and also found that Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with LDL or endotoxin (80, 87, 93).”
Interplay between inflammation and thrombosis in cardiovascular pathology
Stark, K., & Massberg, S. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00552-1 · Cited by 1,033
Brain immunology and immunotherapy in brain tumours
Sampson, J. H., Gunn, M. D., Fecci, P. E., & Ashley, D. M. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0224-7 · Cited by 758
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Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions
Raggi, P., Genest, J. J., Giles, J. T., Rayner, K. J., Dwivedi, G., Beanlands, R. S., & Gupta, M. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.07.014 · Cited by 447
Metadata
- Authors
- Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J.
- Affiliations
- Queen's University (CA)
- Sunnybrook Health Science Centre (CA)
- Corresponding author
- Rauh, Michael J.
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 55
- Pages
- 56-70.e13
- ISSN
- 0301-472X (ISSN-L)
- OpenAlex
- W2749902186
- Cited by
- 295
- References
- 62
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 34 · 2023: 37 · 2022: 43 · 2021: 37 · 2020: 34 · 2019: 24 · 2018: 17 · 2017: 7
- FWCI
- 17.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Experimental Hematology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Queen's University
- Canada Foundation for Innovation
- Ontario Institute for Cancer Research
- Southeastern Ontario Academic Medical Organization
- Women's Giving Circle/University Hospitals Kingston Foundation
- Queen's University Terry Fox Foundation Training Program in Transdisciplinary Cancer Research
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- TET2, macrophages, inflammation resolution, 5-hydroxymethylcytosine, DNA demethylation, clonal hematopoiesis of indeterminate potential, myelodysplastic syndrome, chronic myelomonocytic leukemia, lipopolysaccharide response, NF-κB, interleukin-6, IL-1β, arginase-1, alternative macrophage activation, epigenetic dysregulation
- MeSH terms
- Animals, Arginase, Cell Differentiation, Cell Line, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Mutation, Myelodysplastic Syndromes, Proto-Oncogene Proteins, Leukemia, Myelomonocytic, Chronic, Interleukin-6, Mice, Knockout, Dioxygenases, Interleukin-1beta
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