Journal Article

SOX9 plays an essential role in myofibroblast driven hepatic granuloma integrity and parenchymal repair during schistosomiasis-induced liver damage

Jokl, Elliot, Simpson, Kara, Costain, Alice, MacDonald, Andrew S., Phythian-Adams, Alexander, Couper, Kevin N., Su, Kim, Cheeseman, Antonn, Piper Hanley, Karen

2025

Overview

Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following Schistosoma mansoni infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both naïve and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6c lo monocyte populations in infected SOX9 deficient mice only. Infected SOX9–deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and/or reverse fibrotic disease.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Bile ducts / Biology and Life Sciences / Care and treatment / Collagen / Complications and side effects / Deposition / Development and progression / Eggs / Eosinophilia / Extracellular matrix / Extracellular Matrix - metabolism / Female / Fibroblasts / Granuloma / Granuloma - metabolism / Granuloma - parasitology / Granuloma - pathology / Granulomas / Health aspects / Hepatocytes / Hypertension / Immune system / Infections / Lethality / Leukocytes (neutrophilic) / Liver / Liver - metabolism / Liver - parasitology / Liver - pathology / Liver cirrhosis / Liver diseases / Male / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Monocytes / Myofibroblasts - metabolism / Myofibroblasts - parasitology / Myofibroblasts - pathology / Parasites / Parasitic diseases / Schistosoma mansoni / Schistosomiasis / Schistosomiasis mansoni - metabolism / Schistosomiasis mansoni - pathology / Secretions / Sox9 protein / SOX9 Transcription Factor - genetics / SOX9 Transcription Factor - metabolism / Therapeutic targets / Transcription factors / Tropical diseases