IL-4/IL-4Rα signaling activates PPARγ to promote oligodendrocyte differentiation and remyelination

The restoration of white matter damage is essential for the functional recovery observed in demyelinating diseases such as multiple sclerosis (MS). Interleukin 4 (IL-4), a type II cytokine, has been acknowledged for its protective role in modulating microglia and immune cells, thus suppressing inflammatory processes. Emerging evidence suggests that IL-4 extends beyond its immunomodulatory function, playing a part in memory, neuronal pruning, protection, and neurodegeneration. Here, our study identified the capacity of IL-4 to stimulate myelinogenesis and remyelination in the central nervous system. We observed dynamic changes in IL-4Rα expression during both developmental myelination and remyelination. Intranasal IL-4 administration during a critical postnatal period significantly enhanced myelination. Following demyelination induced by lysophosphatidylcholine, IL-4 was found to augment remyelination and restore motor function. Using genetic knockout experiments in vitro, we further showed that IL-4 binding to IL-4Rα and activating the PPARγ signaling pathway, thereby upregulating GPNMB, a downstream effector that promotes oligodendrocyte differentiation and myelination. These findings reveal a novel protective role for IL-4 in CNS repair, extending beyond its established functions in microglia, macrophages, or neurons. Intranasal IL-4 delivery may represent a promising therapeutic strategy for enhancing white matter integrity in leukodystrophies and MS. Abbreviations: MS, multiple sclerosis; IL-4, Interleukin 4; CNS, central nervous system; OPCs, oligodendrocytes precursor cells; IL-4R, IL-4 receptor; i.n., intranasal; LPC, lysophosphatidylcholine; PVL, periventricular leukomalacia; EAE, experimental autoimmune encephalomyelitis; dpi, days post immunization; dpl, days post lesion; Nkx2.2, NK2 homeobox 2; Olig2, oligodendrocyte transcription factor 2; OLs, oligodendrocytes; SOX10, SRY-Box Transcription Factor 10; PDGFRα, platelet derived growth factor receptor alpha; CNPase, 2',3'-Cyclic Nucleotide 3' Phosphodiesterase; APC, adenomatous polyposis coli; ASPA, aspartoacylase; GFAP, glial fibrillary acidic protein; Iba1, ionized calcium binding adaptor molecule 1; MBP, myelin basic protein; TEM, transmission electron microscopy; CC, corpus callosum; GCC, genu of the corpus callosum; CG, cingulum; CTX, cortex; STR, striatum; EC, external capsule; Pre-OLs, pre-myelinating oligodendrocytes; STAT6, signal transducer and activator of transcription 6; Pio, pioglitazone; T3, triiodothyronine; CNTF, ciliary neurotrophic factor; PPARγ, peroxisome proliferator-activated receptor γ.