IL-1R1 and IL-18 signals regulate mesenchymal stromal cells in an aged murine model of myelodysplastic syndromes

Abstract

Abstract Myelodysplastic syndromes (MDS) are age-related diseases characterized by bone marrow (BM) dysfunction and an increased risk for developing acute leukemia. Although there is growing evidence that highlight the crucial role of the BM microenvironment (BMME) in MDS, the specific influence of inflammation on BMME changes and the potential benefits of targeting cytokines therapeutically remain to be elucidated. We previously found that interleukin-1 (IL-1) is a driver of aging phenotypes of the BMME and hematopoietic stem and progenitor cells (HSPCs). In this study, BM samples from patients with MDS demonstrated upregulated levels of IL-1 family cytokines, including IL-18. Using highly purified primary BM-derived mesenchymal stromal cells (MSCs), both IL-1b and IL-18 were found to exert direct effects on MSCs, thus influencing their ability to support HSPCs and erythroid progenitors. This confirms the significant involvement of both these IL-1 family cytokines in regulating the BM niche. Furthermore, targeting IL-1 receptor type 1 mitigated these aging phenotypes in older mice. We subsequently employed an age-appropriate murine model of MDS by transplanting NUP98-HOXD13 transgenic mice (NHD13Tg) cells into aged wild-type mice. Treatment with inhibitors that targeted IL-1 receptor-associated kinase 4 (IRAK4) and NOD-like receptor family pyrin domain containing 3 (NLRP3) reversed the proliferation of dysfunctional MSCs and enhanced their functionality. In addition, IRAK4 inhibition selectively suppressed MDS clonal cells while sparing non-MDS cells in the BM. These findings suggest that targeting IL-1 signaling holds promise for MDS treatment by addressing the underlying myeloid malignancy and restoring the altered BMME via BM-MSCs.