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Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis
Open accessAbstract
Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease. Liu et al. report that the IL-6R antibody reduces the atherosclerosis promoted by Tet2 clonal hematopoiesis (CH) via reversal of increased macrophage colony-stimulating factor 1 receptor expression and suggests blocking IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.
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TL;DR
In a mouse model of Tet2-deficient clonal hematopoiesis, IL-6 receptor blockade reversed accelerated atherosclerosis, monocytosis, lesional macrophage burden, and CSF1R expression. The proposed mechanism is IL-6-induced STAT3 binding to the Csf1r promoter in Tet2-deficient macrophages, increasing CSF1R-dependent macrophage survival; CSF1R inhibition also reversed atherosclerosis.
Key findings
- IL-6R antibody treatment in Tet2 CH mice reversed monocytosis, reduced aortic monocytes/macrophages, eliminated the significant increase in aortic root lesion area, reversed increased lesional macrophage staining, and increased fibrous cap area; it did not alter necrotic core area or lesional IL-1β.
- Tet2 CH increased CSF1R staining in lesional macrophages and on bone marrow monocytes, and increased CSF1R expression in HSPC subsets; IL-6R antibody reversed these increases.
- In Tet2-deficient macrophages, IL-6 increased Csf1r mRNA and STAT3 binding to the Csf1r promoter; increased nuclear acetylated STAT3 was observed, and HDAC inhibition with TSA increased STAT3 acetylation, promoter binding, and Csf1r mRNA in control macrophages.
- CSF1R inhibitor PLX3397 reduced circulating Ly6Chi, Ly6Clo, and total monocytes and completely reversed accelerated atherosclerosis in Tet2 CH mice; in humans with TET2 CH (n = 6) versus healthy individuals (n = 8), CD16+ monocytes showed 1.58-fold higher CSF1R expression (log2 fold change = 0.66, P = 0.0002), with CSF1R positivity in 59% versus 29%.
Methods
- Lethally irradiated Ldlr−/− mice were transplanted with 40% CD45.2 Tet2-deficient bone marrow plus 60% CD45.1 WT bone marrow (Tet2 CH) or control bone marrow, fed a Western diet, and treated with IL-6R-blocking antibody or IgG; a separate cohort received the CSF1R inhibitor PLX3397.
- Mechanistic studies used mouse bone marrow-derived macrophages, Tet2-deficient and control cells, IL-6 treatment, ChIP–qPCR for STAT3 binding to the Csf1r promoter, methylated DNA capture, immunoblotting, flow cytometry, and apoptosis/viability assays.
- Human relevance used CRISPR–Cas9-generated TET2−/− human ESCs and TET2+/− iPSCs differentiated into HSPCs and macrophages, plus scRNA-seq and targeted sequencing of PBMCs from patients with TET2 CH and controls.
Limitations
- The paper states that tocilizumab did not significantly alter CVD risk in the ENTRACTE trial and that tocilizumab raises LDL cholesterol and triglycerides, which may offset benefit; it also notes that Ldlr−/− mice avoid the IL-6-induced reduction in LDLR that may occur in humans.
- The paper states species differences in basal CSF1R protein levels and Akt phosphorylation between mouse and human macrophages, and that the human validation cohort was small (n = 6 TET2 CH, n = 8 healthy); it also states the study was not powered for sex-specific analyses.
- Evident from the text: the causal evidence is primarily from mouse models and cell systems, with no randomized clinical trial of IL-6 or CSF1R blockade in TET2 CH, and the human data are observational and limited in sample size.
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45 Own result · 16 Own interpretation · 11 Check pending · 9 Not checked yet · 7 Own method · 2 No full text of the sources
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice.”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression.”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression.”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression.”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression.”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Abstract
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 29
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Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Results > TET2−/− macrophages show higher CSF1R and resist apoptosis
“in individuals with TET2 CH (n = 6), we found a 1.58-fold higher CSF1R expression among CD16+ monocytes (log2 fold change = 0.66, P = 0.0002), the major monocyte subset expressing CSF1R in humans69, compared to healthy individuals (n = 8)”
§ Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis > Methods > Human sample DNA extraction and CH variant calling
“CHIP mutations were determined via targeted capture panel, resulting in eight TET2 and six control patients.”
Citations
Cites
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482
Self-citationRidker, P. M., Hennekens, C. H., Buring, J. E., & Rifai, N. (2000) · New England Journal of Medicine · doi:10.1056/nejm200003233421202 · Cited by 5,850
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841
McGinnis, C. S., Murrow, L. M., & Gartner, Z. J. (2019) · Cell Systems · doi:10.1016/j.cels.2019.03.003 · Cited by 4,521
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531
Efficacy and safety of low-dose colchicine after myocardial infarction
Tardif, J.-C., Kouz, S., Waters, D. D., Bertrand, O. F., Diaz, R., Maggioni, A. P., Pinto, F. J., Ibrahim, R., Gamra, H., Kiwan, G. S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1912388 · Cited by 3,159
Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease
Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., McConkey, M., Gupta, N., Gabriel, S., Ardissino, D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1701719 · Cited by 2,683
Self-citation
Research works printed but not linked: 1
- Heimlich, J. B. et al. Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis. Preprint at bioRxiv https://doi.org/10.1101/2022.12.01.518580 (2022). · DOI
Cited by
TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer
López-Moyado, I. F., Ko, M., Hogan, P. G., & Rao, A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-080223-044610 · Cited by 123
Yalçınkaya, M., Liu, W., Thomas, L.-A., Olszewska, M., Xiao, T., Abramowicz, S., Papapetrou, E. P., Westerterp, M., Wang, N., Tabas, I. A., et al. (2023) · Circulation · doi:10.1161/circulationaha.123.065344 · Cited by 108
Self-citationColchicine prevents accelerated atherosclerosis in TET2 -mutant clonal haematopoiesis
Zuriaga, M. A., Yu, Z., Matesanz, N., Truong, B. M. T., Ramos-Neble, B. L., Lopez, M., Uddin, M. M., Nakao, T., Niroula, A., Zorita, V., et al. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae546 · Cited by 107
Clonal hematopoiesis and atherosclerosis
Oren, O., Small, A. M., & Libby, P. (2024) · Journal of Clinical Investigation · doi:10.1172/jci180066 · Cited by 78
Self-citationMalignant JAK-signaling: at the interface of inflammation and malignant transformation
Perner, F., Pahl, H. L., Zeiser, R., & Heidel, F. H. (2025) · Leukemia · doi:10.1038/s41375-025-02569-8 · Cited by 72
Metadata
- Authors
- Liu, W., Yalcinkaya, M., Maestre, I. F., Olszewska, M., Ampomah, P. B., Heimlich, J. B., Wang, R., Vela, P. S., Xiao, T., Bick, A. G., Levine, R., Papapetrou, E. P., Libby, P., Tabas, I., Wang, N., & Tall, A. R.
- Affiliations
- Columbia University (US)
- Tisch Cancer Institute (US)
- Vanderbilt University Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Liu, Wenli
- Wang, Nan
- Tall, Alan R.
- ORCID
- Venue
- Nature Cardiovascular Research
- Published
- 2023-06-08
- Volume
- 2
- Issue
- 6
- Pages
- 572-586
- ISSN
- 2731-0590 (ISSN-L)
- PMC
- PMC10399458
- OpenAlex
- W4379878248
- Semantic Scholar
- 3bd13f920fde1647aafffc476ad7e87004a4a6bc
- Cited by
- 93
- References
- 86
- Citations by year
- 2026: 35 · 2025: 37 · 2024: 15 · 2023: 6
- FWCI
- 9.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fondation Leducq (TNE‐18CVD04, 18CVD04)
- Novo Nordisk
- National Institutes of Health
- Genentech
- National Heart, Lung, and Blood Institute (TNE-18CVD04, R01HL118567, R01HL134892, R01HL155431, R35HL145228, R01HL148071, R01HL163099)
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- clonal hematopoiesis, TET2 deficiency, atherosclerosis, IL-6 signaling, IL-6 receptor antibody, CSF1R, macrophages, STAT3, PLX3397, cardiovascular disease, plaque inflammation, monocytosis
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