Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by p...Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by promoting alternative immune activation and improving recovery after SCI in mice.However,cellbased IL-13 delivery is hindered by poor graft survival and limited localisation at the injury site.Here,we developed an injectable hydrogel-based delivery system(HGIL13)composed of IL-13-loaded poly(lactic-co-glycolic acid)(PLGA)microparticles embedded in a photocrosslinkable gelatin methacrylate(GelMA)matrix,enabling sustained and localised IL-13 release.HGIL13 achieved IL-13 release for up to six weeks and significantly reduced lipopolysaccharide(LPS)-induced inflammation in BV2 microglia in vitro.In a mouse contusion SCI model,HGIL13 enhanced functional recovery,reduced lesion volume,and decreased demyelinated area.Using the Hexbtd^(Tomato)mouse we show that HGIL13 modulated the neuroimmune response by decreasing resident microglia density,downregulating CD86 expression,and upregulating Arginase-1 in both microglia and infiltrating monocyte-derived macrophages.RT-qPCR and RNA-seq analyses confirmed sustained immunomodulation over 28 days and indicated early reduction of activated microglia at 7 days post-injury as a key therapeutic mechanism.This study presents a safe,effective,and translatable strategy for localised cytokine delivery,demonstrating strong potential for immunomodulation and improved functional recovery following SCI.展开更多
基金supported by University College Dublin and Taighde ireann-Research Ireland(19/FFP/6642 to DD,16/IA/4584 to DB,and GOIPG/2021/304 to CW)supported by the Medical Research Center Initiative for High Depth Omics,and CURE:JPMXP1323015486 for MIB,and AMRC,Kyushu University+1 种基金by AMED JP23gm1910004,JP23jf0126004,24zf0127012,JSPS KAKENHIJP25H01009Ono Pharmaceutical Foundation for Oncology,Immunology and Neurology,and the Takeda Science Foundation.
文摘Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by promoting alternative immune activation and improving recovery after SCI in mice.However,cellbased IL-13 delivery is hindered by poor graft survival and limited localisation at the injury site.Here,we developed an injectable hydrogel-based delivery system(HGIL13)composed of IL-13-loaded poly(lactic-co-glycolic acid)(PLGA)microparticles embedded in a photocrosslinkable gelatin methacrylate(GelMA)matrix,enabling sustained and localised IL-13 release.HGIL13 achieved IL-13 release for up to six weeks and significantly reduced lipopolysaccharide(LPS)-induced inflammation in BV2 microglia in vitro.In a mouse contusion SCI model,HGIL13 enhanced functional recovery,reduced lesion volume,and decreased demyelinated area.Using the Hexbtd^(Tomato)mouse we show that HGIL13 modulated the neuroimmune response by decreasing resident microglia density,downregulating CD86 expression,and upregulating Arginase-1 in both microglia and infiltrating monocyte-derived macrophages.RT-qPCR and RNA-seq analyses confirmed sustained immunomodulation over 28 days and indicated early reduction of activated microglia at 7 days post-injury as a key therapeutic mechanism.This study presents a safe,effective,and translatable strategy for localised cytokine delivery,demonstrating strong potential for immunomodulation and improved functional recovery following SCI.
