Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal
Open accessAbstract
Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions.
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IL-1β rapidly and robustly induces PU.1 expression in HSC and MPP populations, including MPPGM.
“We found that IL-1β rapidly and robustly induces PU.1 expression in HSC and MPP populations (Pietras et al., 2016), including MPPGM.”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Pietras et al., 2016
In Results, ‘Precocious activation of a PU.1 molecular circuit,’ the paper reports strong, rapid PU.1 induction in IL-1β-treated HSCs, but limited or absent activation in treated MPPs and GMPs. That directly conflicts with the citation’s attribution of robust induction across HSC and MPP populations. The phrase ‘including MPPGM’ follows the citation and appears to describe the citing authors’ own finding. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredChronic pro-inflammatory signaling due to chronic infections or repetitive sterile inflammation is detrimental to HSPC self-renewal, promoting loss of quiescence and differentiation.
“Chronic pro-inflammatory signaling due to chronic infections or repetitive sterile inflammation, however, has been shown to be detrimental to HSPC self-renewal, promoting loss of quiescence and differentiation [61–65].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [62]
The Results sections on haematopoietic remodelling and chronic IL-1 exposure report increased HSC division, myeloid-biased differentiation, and impaired self-renewal after repeated IL-1 treatment in mice. The paper does not establish those combined effects specifically in chronic infection or repetitive sterile inflammation, so the claim extends beyond the condition tested. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIL-1 can stimulate HSC proliferation, driving their myeloid differentiation at the expense of self-renewal, thus eroding their repopulating capacity.
“Indeed, IL-1 can stimulate HSC proliferation, driving their myeloid differentiation at the expense of self-renewal, thus eroding their repopulating capacity.28,49,50”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [28]
The Results sections on IL-1-accelerated differentiation and chronic exposure report faster HSC division, increased myeloid differentiation, and impaired self-renewal and transplantation capacity. But the claim omits the crucial duration qualifier: the Results section on acute stimulation says acute IL-1 exposure promotes myeloid recovery without impairing HSC self-renewal. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLong-term IL-1α treatment significantly impairs HSC self-renewal.
“These data suggest that long-term IL-1α treatment significantly impairs HSC self-renewal, as previously shown28”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [28]
The Results section (‘Chronic IL-1 exposure impairs HSC function’; page unavailable) reports significantly impaired HSC self-renewal after 70 days of treatment. However, the mice received IL-1β, not the IL-1α specified in the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe findings imply the existence of a braking mechanism that limits HSC cell cycle entry in response to chronic inflammatory stress.
“These findings imply the existence of a braking mechanism that limits HSC cell cycle entry in response to chronic inflammatory stress (Pietras et al., 2016; Rabe et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
The Discussion (page unavailable) reports that the HSC pool remains intact after chronic IL-1 exposure and suggests that a quiescent HSC subset may replenish responsive cells. That provides a basis for the citing authors’ inference, but the paper does not identify a braking mechanism limiting cell-cycle entry; the Results instead report increased HSC division after IL-1 treatment. (LLM, conf=0.80)
Experimental — accuracy not yet measured
Previous reports indicate that acute IL-1 administration in vivo triggers cell cycle activity in the SLAM compartment.
“Indeed, previous reports indicate that acute IL-1 administration in vivo triggers cell cycle activity in the SLAM compartment (Hemmati et al., 2019; Pietras et al., 2016; Weisser et al., 2016)”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
In Results (‘Haematopoietic remodelling following IL-1 exposure’), the paper reports increased division of CD48−CD150+ long-term HSCs in vivo after seven consecutive days of IL-1β treatment. It defines acute treatment as one day and reports rapid progenitor expansion then, but does not directly show cell-cycle activity in the SLAM compartment after that acute treatment. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIL-1 has detrimental impacts on WT HSC function.
“Given the contribution of IL-1 to inflammaging and its detrimental impacts on WT HSC function,23,28 we further focused on the IL-1 pathway.”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [28]
Chronic IL-1 increased PU.1 expression and the frequency of PU.1hi SLAM cells.
“Consistent with our prior work, chronic IL-1 increased PU.1 expression and the frequency of PU.1hi SLAM cells (Fig. 3, C and D; Pietras et al., 2016).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
Acute IL-1 exposure drives myeloid cell overproduction in vivo via precocious activation of PU.1 in HSC.
“Previous work from our group demonstrates that acute IL-1 exposure drives myeloid cell overproduction in vivo via precocious activation of the master myeloid transcription factor PU.1 (Pietras et al., 2016) in HSC.”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
IL-1β treatment for 20 d in mice models chronic inflammatory stress.
“isolated from the BM of mice treated with or without IL-1β for 20 d to model chronic inflammatory stress (Fig. 1 A; Pietras et al., 2016; Rabe et al., 2020).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
IL-1 activates precocious myeloid differentiation in HSCs.
“We also previously reported that IL-1 activates precocious myeloid differentiation in HSCs (Pietras et al., 2016)”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Pietras et al., 2016
The mechanism of IL-1β-driven upregulation of Spi1 may be driven by pathways such as NF-κB.
“the mechanism of IL-1β-driven upregulation of Spi1 may be driven by pathways such as NF-κB (Pietras et al., 2016; Etzrodt et al., 2019; Yamashita and Passegue, 2019; Ahmed et al., 2022)”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Pietras et al., 2016
Increased PU.1 expression triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as myeloid-biased hematopoiesis.
“Increased PU.1 expression in turn triggers enhanced activation of myeloid differentiation pathways in HSPC, leading to increased myeloid cell output, sometimes referred to as “myeloid-biased” hematopoiesis (Pietras et al., 2016; Rabe et al., 2020; 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 Pietras et al., 2016
NF-κB is crucial for PU.1 induction in HSC.
“which we and others previously showed to be crucial for PU.1 induction in HSC.”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Pietras et al., 2016
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 Pietras et al., 2016
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“In vitro culture assays Purified HSCLT were cultured using a similar protocol as that previously published (Pietras et al., 2016).”
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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-citationBlood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation
Ahmed, N., Etzrodt, M., Dettinger, P., Kull, T., Loeffler, D., Hoppe, P. S., Chavez, J. S., Zhang, Y., Camargo Ortega, G., Hilsenbeck, O., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20202490 · Cited by 9 · see citing works
Self-citationDeterminants, mechanisms, and functional outcomes of myeloid cell diversity in cancer
Caronni, N., Montaldo, E., Mezzanzanica, L., Cilenti, F., Genua, M., & Ostuni, R. (2021) · Immunological Reviews · doi:10.1111/imr.12944 · Cited by 6 · see citing works
Type 1 interferon perturbates clonal competition by reshaping human blood development
Lama, C., Isakov, D., Rosenberg, S., Quijada-Álamo, M., Saurty-Seerunghen, M. S., Moein, S., Nozais, M., Abera, T.-A., Sakaguchi, O., Totwani, M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02751-3 · Cited by 3 · see citing works
- Authors
- Pietras, E. M., Mirantes-Barbeito, C., Fong, S., Loeffler, D., Kovtonyuk, L. V., Zhang, S., Lakshminarasimhan, R., Chin, C. P., Techner, J.-M., Will, B., Nerlov, C., Steidl, U., Manz, M. G., Schroeder, T., & Passegué, E.
- Affiliations
- University of California, San Francisco (US)
- ETH Zurich (CH)
- University of Zurich (CH)
- Albert Einstein College of Medicine (US)
- University of Oxford (GB)
- Corresponding author
- Pietras, Eric M.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2016-04-25
- Volume
- 18
- Issue
- 6
- Pages
- 607-618
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4884136
- OpenAlex
- W2343868815
- Cited by
- 689
- References
- 9
- Citations by year
- 2026: 64 · 2025: 76 · 2024: 68 · 2023: 87 · 2022: 91 · 2021: 89 · 2020: 74 · 2019: 52 · 2018: 38 · 2017: 38 · 2016: 11
- FWCI
- 44.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (146528, 310030)
- Biotechnology and Biological Sciences Research Council (BB/M024350/1)
- National Heart, Lung, and Blood Institute (R01HL092471, F32HL106989)
- National Cancer Institute (R01CA166429)
- National Institute of Allergy and Infectious Diseases (T32AI007334)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK105134, K01DK098315)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- hematopoietic stem cells, interleukin-1, myeloid differentiation, HSC self-renewal, PU.1, chronic inflammation, bone marrow damage, HSC transplantation, blood homeostasis, inflammatory signaling
- MeSH terms
- Animals, Bone Marrow, Cell Division, Hematopoiesis, Hematopoietic Stem Cells, Interleukin-1, Bone Marrow Transplantation, Cell Lineage, Cell Proliferation, Mice
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