Activating an interleukin 4-FLT3-STAT6 axis in multipotent progenitors restores lymphopoiesis in inflammation and aging

Chronic inflammation and aging skew hematopoiesis toward myelopoiesis at the expense of lymphoid output. We screened type 2 and anti-inflammatory cytokines to identify extrinsic signals capable of restoring lymphoid lineage commitment in hematopoietic stem and progenitor cells (HSPCs). Interleukin 4 (IL-4) specifically inhibited inflammation-induced myelopoiesis and shifted multipotent progenitor (MPP) differentiation toward the lymphoid lineage. IL-4 activated a signal transducer and activator of transcription 6 (STAT6)-dependent transcriptional program in MPPs, increasing the expression of lymphoid-specific genes. Mechanistically, the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3), which is highly expressed in MPPs, interacted with IL-4Rα to facilitate STAT6 activation. In vivo, IL-4 reversed inflammation-induced hematopoietic imbalance and accelerated lymphoid recovery. In aged mice, IL-4 administration shifted the MPP composition toward a lymphoid bias and restored B and T lymphocyte output. Long-term IL-4 treatment in aged mice improved immune, metabolic, physical, and cognitive functions; these rejuvenating effects were recapitulated by transplantation of IL-4-treated HSPCs. Promoting IL-4 signaling in MPPs may enable correction of hematopoietic dysregulation in inflammatory and aging-related conditions.