S100A4 enhances the pro-fibrotic effect of macrophage to promote collagen capsule formation of Trichinella spiralis
- 1Department of Pathogen Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China
Abstract
Background: Trichinella spiralis is a zoonotic parasitic nematode capable of infecting humans and animals, causing trichinellosis. It poses a critical threat to human health, livestock industry and food safety. The muscle larva of T. spiralis is encased within a collagen capsule that is believed to protect it from host immunity. A strong macrophage-dominated inflammatory infiltrate accumulates around the capsule, yet how macrophages contribute to capsule formation remains unclear. Our objective was to investigate the effect of macrophage on collagen capsule formation. Methodology/Principal findings: The results of immunofluorescence showed that S100A4 ⁺ cells accumulated in T. spiralis-infected muscle, and were composed predominantly of CD206 ⁺ macrophages. These macrophages were positioned in direct contact with α-SMA+ myofibroblasts. Moreover, numerous cells positive for both CD206 (M2 macrophage canonical marker) and α‑smooth muscle actin (α-SMA, biomarker of myofibroblasts) were observed. Western blot analysis revealed that S100A4 expression was restricted chiefly to M2 macrophage and its expression was markedly amplified by IL-4 together with excretory–secretory (ES) products from muscle larvae of T. spiralis. qPCR showed that inhibiting S100a4 transcription reduced Arg1 mRNA levels in macrophages activated by ES and IL-4. Immunofluorescence and western blot analysis showed the activated macrophages induced modest upregulation of α-SMA in fibroblasts. Immunohistochemistry revealed that inhibition of S100A4 by niclosamide reduced the expressions of CD206, TGF-β1 and collagen I in T. spiralis-infected muscle. Compared with albendazole alone, the combination of niclosamide and albendazole further reduced the larval burden in T. spiralis-infected mice. Conclusions/Significance: In conclusion, infection with T. spiralis significantly upregulated S100A4 expression in skeletal muscle-infiltrating macrophages. S100A4 further promoted macrophage M2 polarization. The M2-like macrophages either drove fibroblast activation or acquired myofibroblast-like features, thereby fostering collagen capsule formation. Blocking S100A4 diminished macrophage M2 polarization, prevented collagen capsule formation, and represented a potential adjunctive strategy against trichinellosis. Author summary: It is well known that T. spiralis provokes a robust inflammatory response encircling the collagen capsule that houses the muscle larva in skeletal muscle. The role of inflammatory cells in collagen capsule formation is debated. In this study, we revealed that macrophages densely accumulated around the muscle larvae of T. spiralis. The muscle larvae increased skeletal muscle IL‑4 levels to drive the expression of S100A4 in macrophages. S100A4 further enhanced macrophage M2 polarization. M2-like macrophages induced fibroblast‑to‑myofibroblast transition by secreting S100A4 and TGF-β1, or directly converted into myofibroblast-like cells, which synthesized the extracellular matrix components (ECM) and thereby fostering collagen capsule formation. Inhibition of S100A4 by niclosamide robustly attenuated infection-triggered collagen deposition and concurrently enhanced the efficacy of albendazole against T. spiralis muscle larvae.
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BibTeX
@article{gao2026s100a4,
title = {{S100A4 enhances the pro-fibrotic effect of macrophage to promote collagen capsule formation of Trichinella spiralis}},
author = {Meng Ying Gao and Chen Chen Dong and Yue Chun Tang and Ruo Qi Wang and Li Wang and You Jia Ge and Qiao Yu Geng and Peng Jiang and Zi Fang Zhang},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = sep,
doi = {10.1371/journal.pntd.0014647},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014647},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - S100A4 enhances the pro-fibrotic effect of macrophage to promote collagen capsule formation of Trichinella spiralis
AU - Meng Ying Gao
AU - Chen Chen Dong
AU - Yue Chun Tang
AU - Ruo Qi Wang
AU - Li Wang
AU - You Jia Ge
AU - Qiao Yu Geng
AU - Peng Jiang
AU - Zi Fang Zhang
PY - 2026
DA - 2026/09/15
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014647
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014647
AB - Background: Trichinella spiralis is a zoonotic parasitic nematode capable of infecting humans and animals, causing trichinellosis. It poses a critical threat to human health, livestock industry and food safety. The muscle larva of T. spiralis is encased within a collagen capsule that is believed to protect it from host immunity. A strong macrophage-dominated inflammatory infiltrate accumulates around the capsule, yet how macrophages contribute to capsule formation remains unclear. Our objective was to investigate the effect of macrophage on collagen capsule formation. Methodology/Principal findings: The results of immunofluorescence showed that S100A4 ⁺ cells accumulated in T. spiralis-infected muscle, and were composed predominantly of CD206 ⁺ macrophages. These macrophages were positioned in direct contact with α-SMA+ myofibroblasts. Moreover, numerous cells positive for both CD206 (M2 macrophage canonical marker) and α‑smooth muscle actin (α-SMA, biomarker of myofibroblasts) were observed. Western blot analysis revealed that S100A4 expression was restricted chiefly to M2 macrophage and its expression was markedly amplified by IL-4 together with excretory–secretory (ES) products from muscle larvae of T. spiralis. qPCR showed that inhibiting S100a4 transcription reduced Arg1 mRNA levels in macrophages activated by ES and IL-4. Immunofluorescence and western blot analysis showed the activated macrophages induced modest upregulation of α-SMA in fibroblasts. Immunohistochemistry revealed that inhibition of S100A4 by niclosamide reduced the expressions of CD206, TGF-β1 and collagen I in T. spiralis-infected muscle. Compared with albendazole alone, the combination of niclosamide and albendazole further reduced the larval burden in T. spiralis-infected mice. Conclusions/Significance: In conclusion, infection with T. spiralis significantly upregulated S100A4 expression in skeletal muscle-infiltrating macrophages. S100A4 further promoted macrophage M2 polarization. The M2-like macrophages either drove fibroblast activation or acquired myofibroblast-like features, thereby fostering collagen capsule formation. Blocking S100A4 diminished macrophage M2 polarization, prevented collagen capsule formation, and represented a potential adjunctive strategy against trichinellosis. Author summary: It is well known that T. spiralis provokes a robust inflammatory response encircling the collagen capsule that houses the muscle larva in skeletal muscle. The role of inflammatory cells in collagen capsule formation is debated. In this study, we revealed that macrophages densely accumulated around the muscle larvae of T. spiralis. The muscle larvae increased skeletal muscle IL‑4 levels to drive the expression of S100A4 in macrophages. S100A4 further enhanced macrophage M2 polarization. M2-like macrophages induced fibroblast‑to‑myofibroblast transition by secreting S100A4 and TGF-β1, or directly converted into myofibroblast-like cells, which synthesized the extracellular matrix components (ECM) and thereby fostering collagen capsule formation. Inhibition of S100A4 by niclosamide robustly attenuated infection-triggered collagen deposition and concurrently enhanced the efficacy of albendazole against T. spiralis muscle larvae.
SN - 1935-2735
ER -