2. Academic Validation
  3. Neuropilin-1 acts as a co-receptor of IL-13 to reprogram macrophages in liver fibrosis

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

  • Pharmacol Res. 2026 Mar:225:108112. doi: 10.1016/j.phrs.2026.108112.
Chenxi Liu 1,  Yingchun Wang 2,  Yinuo Yang 3,  Miaomiao Tian 4,  Tiantian Liu 3,  Songbo Zhao 2,  Le Wang 5,  Lifen Gao 6,  Yuemin Feng 7,  Jianni Qi 8,  Qiang Zhu 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 2 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 3 Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
  • 4 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 5 Department of Health Care Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 6 Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunity, and Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 7 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. Electronic address: [email protected].
  • 8 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. Electronic address: [email protected].
  • 9 Department of Infectious Disease, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. Electronic address: [email protected].
PMID: 41620153 DOI: 10.1016/j.phrs.2026.108112
Abstract

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.

Keywords

Fibrosis; Interleukin-13 receptor alpha1; Macrophage; Neuropilin-1; Reprogramming.

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