Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis
Open accessAbstract
Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and progressive destruction of joint tissue. It is also characterized by aberrant blood phenotypes including anemia and suppressed lymphopoiesis that contribute to morbidity in RA patients. However, the impact of RA on hematopoietic stem cells (HSC) has not been fully elucidated. Using a collagen-induced mouse model of human RA, we identified systemic inflammation and myeloid overproduction associated with activation of a myeloid differentiation gene program in HSC. Surprisingly, despite ongoing inflammation, HSC from arthritic mice remain in a quiescent state associated with activation of a proliferation arrest gene program. Strikingly, we found that inflammatory cytokine blockade using the interleukin-1 receptor antagonist anakinra led to an attenuation of inflammatory arthritis and myeloid expansion in the bone marrow of arthritic mice. In addition, anakinra reduced expression of inflammation-driven myeloid lineage and proliferation arrest gene programs in HSC of arthritic mice. Altogether, our findings show that inflammatory cytokine blockade can contribute to normalization of hematopoiesis in the context of chronic autoimmune arthritis.
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Activation of the quiescent HSC gene program relies, at least in part, on IL-1 signaling.
“Interestingly, activation of this gene program relies, at least in part, on IL-1 signaling (Hernandez et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Hernandez et al., 2020
The Results section on cytokine blockade (page unavailable) reports that the IL-1 receptor blocker anakinra partially normalized expression of proliferation-arrest genes in HSC from mice with collagen-induced arthritis. This supports a possible contribution from IL-1 signaling, but the paper does not establish that activation of the program relies on it: HSC cell-cycle distribution was unchanged, and the Discussion says anakinra’s effects could be indirect. (LLM, conf=0.84)
Experimental — accuracy not yet measuredUsing a mouse model of chronic rheumatoid arthritis, myeloid cell production and accompanying PU.1-driven myeloid gene programs in HSC can be blocked pharmacologically using the IL-1 receptor antagonist anakinra.
“Using a mouse model of chronic rheumatoid arthritis, we previously showed that myeloid cell production and accompanying PU.1-driven myeloid gene programs in HSC can be blocked pharmacologically using the IL-1 receptor (IL-1R) antagonist anakinra (Hernandez et al., 2020).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Hernandez et al., 2020
The Results section on cytokine blockade reports that anakinra reduced myeloid expansion in mice with collagen-induced arthritis and significantly decreased PU.1 and its target genes in HSC. The paper describes these effects as attenuation or partial reversal, not complete blockade; it also does not establish that anakinra acts directly on HSC. (LLM, conf=0.86)
Experimental — accuracy not yet measuredQuiescent HSCs downregulate numerous protein synthesis and cell proliferation genes in a mouse model of chronic rheumatoid arthritis.
“We recently found that quiescent HSCs downregulate numerous protein synthesis and cell proliferation genes in a mouse model of chronic rheumatoid arthritis (Hernandez et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Hernandez et al., 2020
PU.1 plays a key role in emergency myelopoiesis.
“We and others have shown that PU.1 plays a key role in this process (Pietras et al., 2016; Yamashita and Passegue, 2019; Hernandez et al., 2020; Rabe et al., 2020; Chavez et al., 2021; Ahmed et al., 2022; Chavez et al., 2022).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Hernandez et al., 2020
IL-1R blockade could reduce the expression of PU.1 target genes in HSC closer to homeostatic levels, with concurrent reductions in myeloid output.
“Along these lines, we recently showed that IL-1R blockade could reduce the expression of PU.1 target genes in HSC closer to homeostatic levels, with concurrent reductions in myeloid output (Hernandez et al., 2020).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Hernandez et al., 2020
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Self-citationPU.1 is required to restrain myelopoiesis during chronic inflammatory stress
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“1 plays a key role in this process (Pietras et al., 2016; Yamashita and Passegue, 2019; Hernandez et al., 2020; Rabe et al., 2020; Chavez et al., 2021; Ahmed et al., 2022; Chavez et al., 2022).”
BackgroundMethodInfluentialSelf-citationAkkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL‐1R/TLR signals
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Panwar, P., Andrault, P.-M., Saha, D., & Brömme, D. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17312 · Cited by 10 · see citing works
Rapid activation of hematopoietic stem cells
Thapa, R., Elfassy, E., Olender, L., Sharabi, O., & Gazit, R. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03377-6 · Cited by 8 · see citing works
Dysregulation of B lymphocyte development in the SKG mouse model of rheumatoid arthritis
Kim, J. E., Tung, L. T., Jiang, R. R., Yousefi, M., Liang, Y., Malo, D., Vidal, S. M., & Nijnik, A. (2023) · Immunology · doi:10.1111/imm.13691 · Cited by 8 · see citing works
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Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis
López‐Santalla, M., Conde, C., Rodríguez-Trillo, Á., & Garin, M. I. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.943293 · Cited by 6 · see citing works
Mechanisms of Stem Cells and Their Secreted Exosomes in the Treatment of Autoimmune Diseases
Lin, S. J., Wang, K., Pan, X.-H., & Ruan, G. (2024) · Current Stem Cell Research & Therapy · doi:10.2174/011574888x271344231129053003 · Cited by 4 · see citing works
Hypersensitivity response has negligible impact on Hematopoietic Stem Cells
Bujanover, N., Thapa, R., Goldstein, O., Olender, L., Sharabi, O., Milsom, M. D., & Gazit, R. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.06.013 · Cited by 3 · see citing works
Milsom, M. D., & Essers, M. A. G. (2023) · Cells and Development · doi:10.1016/j.cdev.2023.203844 · Cited by 4 · see citing works
Fosl2 Deficiency Predisposes Mice to Osteopetrosis, Leading to Bone Marrow Failure
Chen, J. X., Wen, Y., Lin, L., Cui, Y., Chen, Z., Gao, J., Zhuang, Y., & Chen, Q. (2024) · The Journal of Immunology · doi:10.4049/jimmunol.2300592 · Cited by 3 · see citing works
Lomovskaya, Y. V., Krasnov, K. S., Kobyakova, M. I., Kolotova, A. A., Ermakov, A. M., Сенотов, А. С., Fadeeva, I. S., Fetisova, E. I., Lomovsky, A. I., Zvyagina, A. I., et al. (2024) · Acta Naturae · doi:10.32607/actanaturae.27317 · Cited by 3 · see citing works
Gao, S., Zhang, Y., Ge, Y., Lu, H. Z., & Li, M. (2024) · Medicine · doi:10.1097/md.0000000000040604 · Cited by 3 · see citing works
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Lora, M., Ménard, H. A., Nijnik, A., Langlais, D., Hudson, M., & Colmegna, I. (2025) · Clinical and Translational Science · doi:10.1111/cts.70233 · Cited by 2 · see citing works
Trained Immunity Affecting Dendritic Cell Differentiation and Function in Rheumatoid ArthritisPreprint
Tung, L. T., Jiang, R. R., Pozzebon, B., Mancini, M., Droin, L., Yousefi, M., Kim, J. E., Mousa, M., Liang, Y., Krawczyk, C. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.28.640673 · Cited by 2 · see citing works
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Rapid Activation of Hematopoietic Stem CellsPreprint
Thapa, R., Elfassy, E., Olender, L., Sharabi, O., & Gazit, R. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.01.494258
Additional file 1 of Rapid activation of hematopoietic stem cells
Thapa, R., Elfassy, E., Olender, L., Sharabi, O., & Gazit, R. (2024) · Figshare · doi:10.6084/m9.figshare.26594705
Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cellsPreprint
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Self-citationÉtude phénotypique et fonctionnelle des progéniteurs myéloïdes dans la drépanocytose
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Reversible loss of hematopoietic stem cells transplant potency by chronic Salmonella infection
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IL-1-mediated cancer-adapted hematopoiesis in aging and clonal hematopoiesis
Caiado, F., Gonullu, N. G., & Manz, M. G. (2026) · Seminars in Immunology · doi:10.1016/j.smim.2026.102055
Cradle of rebellion: the relationship between bone marrow microenvironment and autoimmune diseases
Wang, Q., Cheng, J., Gu, Z., & Chen, D. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1760577
- Authors
- Hernandez, G., Mills, T. S., Rabe, J. L., Chavez, J. S., Kuldanek, S., Kirkpatrick, G., Noetzli, L., Jubair, W. K., Zanche, M., Myers, J. R., Stevens, B. M., Fleenor, C. J., Adane, B., Dinarello, C. A., Ashton, J., Jordan, C. T., Di Paola, J., Hagman, J. R., Holers, V. M., Kuhn, K. A., & Pietras, E. M.
- Affiliations
- University of Colorado Anschutz (US)
- University of Rochester (US)
- National Jewish Health (US)
- Corresponding author
- Pietras, Eric M.
- ORCID
- Venue
- Haematologica
- Published
- 2019-05-17
- Volume
- 105
- Issue
- 3
- Pages
- 585-597
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC7049366
- OpenAlex
- W2945652237
- Cited by
- 58
- References
- 57
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 12 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 4 · 2019: 3
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (F31HL138754)
- National Cancer Institute (P30CA046934)
- National Institute of Allergy and Infectious Diseases (R01AI098417)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119394, K01DK098315)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR051749, R01AR075033, T32AR007534)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- rheumatoid arthritis, hematopoietic stem cells, myeloid expansion, anakinra, interleukin-1 receptor antagonist, cytokine inhibition, bone marrow, collagen-induced arthritis, chronic inflammation
- MeSH terms
- Animals, Arthritis, Experimental, Arthritis, Rheumatoid, Autoimmune Diseases, Disease Models, Animal, Humans, Cytokines, Mice
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