Pediatrics and neonatology · 2026
Antimicrobial peptide LL37 ameliorated experimental inflammation induced neonatal lung injury through macrophage immunomodulation.
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Zhang Xiaoling, Wang Zhu, Xiao Shuzhe, Li Yongsheng, Ren Zhuxiao, Chuan Nie
Аннотация
BACKGROUND: Previous studies have shown that the lung tissues of preterm infants with bronchopulmonary dysplasia (BPD) are infiltrated by pro-inflammatory macrophages. The Wnt5a/frizzled-5/CaMKII signaling pathway plays a critical role in regulating macrophage activation. The antimicrobial peptide LL37, an important paracrine factor secreted by cord blood mesenchymal stem cells, modulates macrophages. Lower LL37 levels are associated with a higher risk of BPD. However, whether LL37 protects against inflammation-induced lung injury and its underlying mechanisms remain unclear.
METHODS: Macrophages derived from human myeloid leukemia mononuclear cells (THP-1) and human type II alveolar epithelial cells (A549) were co-cultured. Lipopolysaccharide (LPS) and/or LL37 were added, and CRISPR-Cas9 was used to silence Wnt5a expression in THP-1 cells. An inflammation-induced lung injury mouse model was established by the intraperitoneal injection of LPS during early life after birth. Mice were treated with intraperitoneal injections of either LL37 or an LL37-neutralizing antibody. Inflammatory cytokine expression, macrophage phenotypes, apoptosis, proliferation of type II alveolar epithelial cells, and expression of the Wnt5a/frizzled-5/CaMKII pathway were investigated. In addition, macrophage infiltration and polarization as well as alveolar development in mouse lung tissues were assessed.
RESULTS: After LL37 intervention or Wnt5a gene silencing, the expression of inflammatory cytokines in THP-1 cells decreased, pro-inflammatory macrophages decreased, and anti-inflammatory macrophages increased. In the mouse model, LL37 treatment reduced macrophage infiltration, pulmonary alveolar diameter, and the severity of lung fibrosis. The protective effect of LL37 was partially neutralized by the addition of an LL37-neutralizing antibody. LL37 intervention inhibited the Wnt5a/frizzled-5/CaMKII pathway.
CONCLUSION: LL37 ameliorated inflammation-induced lung injury by inhibiting macrophage activation and the inflammatory response. This protective effect may be mediated through downregulation of the macrophage Wnt5a/frizzled-5/CaMKII pathway. These findings provide novel insights and potential targets for the early prevention of lung injury and establish a foundation for translational research on stem cell therapy for BPD.
METHODS: Macrophages derived from human myeloid leukemia mononuclear cells (THP-1) and human type II alveolar epithelial cells (A549) were co-cultured. Lipopolysaccharide (LPS) and/or LL37 were added, and CRISPR-Cas9 was used to silence Wnt5a expression in THP-1 cells. An inflammation-induced lung injury mouse model was established by the intraperitoneal injection of LPS during early life after birth. Mice were treated with intraperitoneal injections of either LL37 or an LL37-neutralizing antibody. Inflammatory cytokine expression, macrophage phenotypes, apoptosis, proliferation of type II alveolar epithelial cells, and expression of the Wnt5a/frizzled-5/CaMKII pathway were investigated. In addition, macrophage infiltration and polarization as well as alveolar development in mouse lung tissues were assessed.
RESULTS: After LL37 intervention or Wnt5a gene silencing, the expression of inflammatory cytokines in THP-1 cells decreased, pro-inflammatory macrophages decreased, and anti-inflammatory macrophages increased. In the mouse model, LL37 treatment reduced macrophage infiltration, pulmonary alveolar diameter, and the severity of lung fibrosis. The protective effect of LL37 was partially neutralized by the addition of an LL37-neutralizing antibody. LL37 intervention inhibited the Wnt5a/frizzled-5/CaMKII pathway.
CONCLUSION: LL37 ameliorated inflammation-induced lung injury by inhibiting macrophage activation and the inflammatory response. This protective effect may be mediated through downregulation of the macrophage Wnt5a/frizzled-5/CaMKII pathway. These findings provide novel insights and potential targets for the early prevention of lung injury and establish a foundation for translational research on stem cell therapy for BPD.