IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging
Summary: Inflammatory cues affect hematopoietic stem cell (HSC) homeostasis and drive proliferation and myeloid skewing of HSCs. The HSC niche in the bone marrow (BM) is populated by a variety of stromal and immune cells that sense and respond to cellular stress. We investigated how BM-resident type...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-05-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422500639X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850043838374084608 |
|---|---|
| author | Pascal Naef Carla A. Jaeger-Ruckstuhl Noah Schnüriger Stefan Forster Inês Monteiro Daniel Brigger Alexander Eggel Kai Kessenbrock Carsten Riether Adrian F. Ochsenbein |
| author_facet | Pascal Naef Carla A. Jaeger-Ruckstuhl Noah Schnüriger Stefan Forster Inês Monteiro Daniel Brigger Alexander Eggel Kai Kessenbrock Carsten Riether Adrian F. Ochsenbein |
| author_sort | Pascal Naef |
| collection | DOAJ |
| description | Summary: Inflammatory cues affect hematopoietic stem cell (HSC) homeostasis and drive proliferation and myeloid skewing of HSCs. The HSC niche in the bone marrow (BM) is populated by a variety of stromal and immune cells that sense and respond to cellular stress. We investigated how BM-resident type 2 innate lymphoid cells (ILC2s) regulate HSC homeostasis and differentiation in steady state, during aging, and after genotoxic stress. We documented that PDGFR-α+sca-1+ mesenchymal stromal cells in the BM produced interleukin (IL)-33 with elevated levels after irradiation and during aging. IL-33/ST2 signaling in BM-resident ILC2s activated MAPK/NF-κB/JAK-STAT signaling and induced cytokine secretion. IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF), secreted by ILC2s, promoted HSCs to proliferate and differentiate into the myeloid lineage. Taken together, we identified that IL-33 produced by MSCs induced ILC2s to secrete myeloid differentiation factors leading to myeloid-skewed HSCs with reduced self-renewal during aging. |
| format | Article |
| id | doaj-art-98ec8a7e558d4b14b25e3b1f0f3d01d9 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-98ec8a7e558d4b14b25e3b1f0f3d01d92025-08-20T02:55:07ZengElsevieriScience2589-00422025-05-0128511237810.1016/j.isci.2025.112378IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and agingPascal Naef0Carla A. Jaeger-Ruckstuhl1Noah Schnüriger2Stefan Forster3Inês Monteiro4Daniel Brigger5Alexander Eggel6Kai Kessenbrock7Carsten Riether8Adrian F. Ochsenbein9Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USADepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, 3012 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, 3008 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, 3008 Bern, SwitzerlandDepartment of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USADepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, SwitzerlandDepartment for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland; Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Corresponding authorSummary: Inflammatory cues affect hematopoietic stem cell (HSC) homeostasis and drive proliferation and myeloid skewing of HSCs. The HSC niche in the bone marrow (BM) is populated by a variety of stromal and immune cells that sense and respond to cellular stress. We investigated how BM-resident type 2 innate lymphoid cells (ILC2s) regulate HSC homeostasis and differentiation in steady state, during aging, and after genotoxic stress. We documented that PDGFR-α+sca-1+ mesenchymal stromal cells in the BM produced interleukin (IL)-33 with elevated levels after irradiation and during aging. IL-33/ST2 signaling in BM-resident ILC2s activated MAPK/NF-κB/JAK-STAT signaling and induced cytokine secretion. IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF), secreted by ILC2s, promoted HSCs to proliferate and differentiate into the myeloid lineage. Taken together, we identified that IL-33 produced by MSCs induced ILC2s to secrete myeloid differentiation factors leading to myeloid-skewed HSCs with reduced self-renewal during aging.http://www.sciencedirect.com/science/article/pii/S258900422500639XImmune responseCell biology |
| spellingShingle | Pascal Naef Carla A. Jaeger-Ruckstuhl Noah Schnüriger Stefan Forster Inês Monteiro Daniel Brigger Alexander Eggel Kai Kessenbrock Carsten Riether Adrian F. Ochsenbein IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging iScience Immune response Cell biology |
| title | IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging |
| title_full | IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging |
| title_fullStr | IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging |
| title_full_unstemmed | IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging |
| title_short | IL-33/ST2 signaling in ILC2s drives exhaustion and myeloid skewing of HSCs in response to hematopoietic stress and aging |
| title_sort | il 33 st2 signaling in ilc2s drives exhaustion and myeloid skewing of hscs in response to hematopoietic stress and aging |
| topic | Immune response Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S258900422500639X |
| work_keys_str_mv | AT pascalnaef il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT carlaajaegerruckstuhl il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT noahschnuriger il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT stefanforster il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT inesmonteiro il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT danielbrigger il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT alexandereggel il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT kaikessenbrock il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT carstenriether il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging AT adrianfochsenbein il33st2signalinginilc2sdrivesexhaustionandmyeloidskewingofhscsinresponsetohematopoieticstressandaging |