Postdoctoral Fellow Boston Children's Hospital Boston, Massachusetts, United States
Disclosure(s):
Jingfei Yao, PhD: No relevant disclosure to display
Introduction/Rationale: 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.
