IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice
| Autor: | Fatima Al-Shahrour, Larisa V. Kovtonyuk, Emma Slack, Hitoshi Takizawa, Markus G. Manz, Eva-Maria Manz, Patrick M. Helbling, César Nombela-Arrieta, Francisco Caiado, Steffen Boettcher, Santiago García-Martín |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Aging
Myeloid Interleukin-1beta Immunology Population Biology Biochemistry Mice Immune system Interleukin-1alpha medicine Animals education Cellular Senescence Inflammation Mice Knockout education.field_of_study Microbiota Hematopoietic stem cell Cell Biology Hematology Hematopoietic Stem Cells Hematopoiesis Transplantation Haematopoiesis medicine.anatomical_structure Cancer research Bone marrow Stem cell |
| Zdroj: | Blood. 139:44-58 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2021011570 |
| Popis: | Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness in the hematopoietic stem cell (HSC) population and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice in contrast to young SPF mice produce more interleukin-1a and interleukin-1b (IL-1a/b) in steady-state bone marrow (BM), with most of the IL-1a/b being derived from myeloid BM cells. Furthermore, blood from steady-state older SPF WT mice contains higher levels of microbe-associated molecular patterns, specifically TLR4 and TLR8 ligands. In addition, BM myeloid cells from older mice produce more IL-1b in vitro, and older mice show higher and more durable IL-1a/b responses upon stimulation with lipopolysaccharide in vivo. To test whether HSC aging is driven by IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knockout (KO) mice. Indeed, older HSCs from IL-1R1KO mice show significantly mitigated aging-associated inflammatory signatures. Moreover, HSCs from older IL-1R1KO and from germ-free mice maintain unbiased lymphomyeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in older WT mice was similarly sufficient to reverse myeloid-biased output of their HSC populations. Collectively, our data define the microbiome/IL-1/IL-1R1 axis as a key, self-sustaining and also therapeutically partially reversible driver of HSC inflammaging. |
| Databáze: | OpenAIRE |
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