Rejuvenating the Aged Hematopoietic System: IL-4 Signaling Restores Lymphopoiesis and Systemic Function 2302788

Abstract Introduction Chronic inflammation and aging disrupt hematopoietic homeostasis, creating a persistent “myeloid bias” that perpetuates immune dysfunction. While the drivers of this skew are well-characterized, strategies to reverse it remain elusive. We hypothesize that anti-inflammatory cytokines act as a fundamental “reset” mechanism, capable of reprogramming hematopoietic stem and progenitor cells (HSPCs) to counteract myeloid skewing and actively restore lymphoid commitment. Methods We utilized in vitro differentiation assays and in vivo models, including LPS-induced inflammation and aging. Hematopoietic stem and progenitor cell (HSPC) subsets were analyzed via flow cytometry and the transcriptomic change in STAT6-KO or IL-4 injected mice. Cellular specificity was dissected using lineage-tracing and bone marrow transplantation. Functional rejuvenation was assessed via cognitive, motor, and metabolic profiling following IL-4 administration. Results We found that IL-4 signaling effectively resolved the inflammation- and aging-driven myeloid bias by promoting lymphoid differentiation in multipotent progenitors (MPPs), but not in hematopoietic stem cells (HSCs). Mechanistically, FLT3 functionally cooperated with the IL-4 receptor to potentiate STAT6 phosphorylation and activation in a cell-intrinsic manner within MPPs, upregulating lymphoid-specific genes while suppressing myeloid programs. Strikingly, systemic IL-4 treatment rejuvenated the aged hematopoietic system, restoring B and T cell output to youthful levels. This hematopoietic restoration translated into systemic benefits, including measurable improvements in cognitive performance, motor coordination, and metabolic parameters in aged mice. Conclusion Our findings identify the IL-4-FLT3-STAT6 signaling axis as a critical regulator of MPP lineage plasticity. This study positions IL-4 as a promising therapeutic agent for correcting hematopoietic dysregulation and mitigating the systemic functional decline associated with inflammaging. Funding Source the Milky Way Research Foundation and the Howard Hughes Medical Institute (HHMI) Topic Categories Hematopoiesis and Immune System Development (HEM)