Neuropilin-1 acts as a co-receptor of IL-13 to reprogram macrophages in liver fibrosis

Neuropilin-1 (NRP-1) is a pleiotropic transmembrane receptor critical in embryonic development of neurological and vascular systems. Increasing evidence suggests that NRP-1 has a major role in immunity. However, the role of NRP-1 in regulating the profibrotic function of macrophages during liver fibrosis has not been defined. In this study, we collected human liver samples from 20 patients with fibrosis and 5 controls, finding significantly elevated NRP-1 expression in macrophages from fibrotic livers. Using macrophage-specific NRP-1 deficient mice subjected to CCl₄-induced liver fibrosis, we demonstrated that NRP-1 deficiency effectively attenuated fibrotic progression. Further experiments revealed that NRP-1 enhances profibrotic macrophage polarization and subsequent hepatic stellate cell activation both in vivo and in vitro. Mechanistically, NRP-1 binds to interleukin-13 receptor alpha1 (IL13Rα1) via its extracellular domain, stabilizing the IL13Rα1-IL13 interaction. This activates IL13 signaling, leading to Tyk2 phosphorylation. The IL13Rα1-Tyk2/Stat6 axis then upregulates the transcription factor EHF, which in turn activates NRP-1 expression in macrophages, establishing a positive feedback loop that amplifies profibrotic functions. Our conclusions indicate that NRP-1 promotes liver fibrosis progression, and targeting macrophage NRP-1 is a potential therapeutic strategy against liver fibrosis. A mechanistic illustration of NRP-1 promoting the reprogramming of profibrotic macrophages and activating HSCs by binding to IL13Rα1, facilitating the IL13Rα1-IL13 interaction, promoting Tyk2 phosphorylation, and forming a positive feedback loop. • Neuropilin-1(NRP-1) expression in macrophages increased in human and mouse tissues with liver fibrosis and positively correlated with the degree of fibrosis. • Macrophage-specific NRP-1 deficiency alleviated liver fibrosis. • NRP-1 promoted macrophage profibrotic polarization and, subsequently, HSCs activation. • NRP-1 bound to Interleukin-13 receptor alpha1 (IL13Rα1), enhancing the stability of the IL13Rα1-IL13 interaction and promoting downstream Tyrosine kinase 2 (Tyk2) phosphorylation, which drives macrophage toward profibrotic phenotype. • The transcription factor EHF was activated by Tyk2 phosphorylation and upregulated the expression of NRP-1 in profibrotic macrophages, completing a positive feedback loop.