IL-1 Mediates Microbiome-Induced Inflamm-Aging of Hematopoietic Stem Cells

Mature blood cells are maintained throughout life by hematopoietic stem cells (HSC). With aging, both HSC self-renewal as well as multi-lineage differentiation fidelity decline, a process determined by cell-intrinsic and –extrinsic factors. We here studied which aging-associated bone marrow (BM) alterations contribute to this process. Aged specific pathogen free (SPF) WT mice have increased systemic levels of microbial compounds compared to their young counterparts. This associates with increased steady-state IL-1a/b production by multiple BM cell populations. Aging-associated inflammatory transcriptional signatures and functional myeloid-differentiation bias in HSCs were mitigated in aged IL-1R1KO SPF and WT germ-free mice. Moreover, myeloid cells from aged mice produce more IL-1b and aged mice show higher and more durable IL-1a/b increase to lipopolysaccharide (LPS) challenges. Reducing inflammatory burden in aged mice by inhibiting IL-1 signaling or by antibiotic treatment rejuvenate HSCs functions. Collectively we define the microbiome-IL-1-IL1R1 axis as a key driver of HSC aging. RNA-sequencing of 30 mice bone marrow haematopoietic stem cells. Three genotypes: wildtype (WTF), bowel germ-free (GF) and IL1R1 KO(IL1RIKO). Three timepoints: 2 month, 1 year and 2 year for WT and KO mice and 2 month and 1 year for GF mice.