Cooperative Interaction Between IL-4 Signaling and FLT3 in Multipotent Progenitors Restore Lymphopoiesis in Inflammation and Aging

Abstract

Hematopoiesis, the process of generating blood cells, is essential for maintaining immune functions in responding to systemic challenges. Disruption of this process, driven by inflammation or aging, often results in myeloid-biased hematopoiesis and impaired lymphoid lineage output. In this study, we identify interleukin-4 (IL-4) signaling as an important modulator of the lymphoid lineage commitment in hematopoietic multipotent progenitors (MPPs). We show that IL-4 promotes MPP differentiation from myelopoiesis to lymphopoiesis via the STAT6 signaling pathway. Transcriptomic analysis reveals that IL-4 signaling upregulates lymphoid-specific pathways while suppressing myeloid differentiation programs in MPPs, but not in hematopoietic stem cells (HSCs). Mechanistically, FLT3-a class III receptor tyrosine kinase highly expressed in MPPs-interacts functionally with IL-4 signaling to facilitate STAT6 phosphorylation and activation. Notably, IL-4 treatment rejuvenates aged hematopoietic stem and progenitor cells, restoring B and T cell output and counteracting inflammaging-associated myeloid bias. These changes are associated with improved immune, metabolic, physical, and cognitive functions, positioning IL-4 signaling-FLT3 cooperation in MPPs as a critical regulator of organism-wide immune fitness. Our findings highlight IL-4 as a potential therapeutic agent for restoring balanced hematopoiesis in the context of aging and inflammation.