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Background <p>Hepatic granuloma formation in <i>Schistosoma mansoni</i> infection is driven by dysregulated cytokine networks and pro-fibrotic signaling pathways, including STAT3, Wnt/β-catenin, and microRNA let-7a circuits. Interleukin-22 (IL-22) is an epithelial-targeted cytokine that signals predominantly through STAT3 and has been implicated in tissue protection and fibrosis modulation. This investigation examined whether IL-22 modulates the STAT3/β-catenin/let-7a molecular axis in schistosomal hepatic granulomas and compared these molecular effects with praziquantel (PZQ) anthelmintic therapy.</p> Methods <p>Male mice infected with <i>S. mansoni</i> were treated with recombinant IL-22 (0.36&#xa0;µg/kg intraperitoneally for 14&#xa0;days), a single oral dose of praziquantel (PZQ, 600&#xa0;mg/kg orally), or both. Serum TNF-α, IL-17, IL-22, and IgE were quantified by ELISA. Hepatic STAT3 and β-catenin mRNA and let-7a miRNA expression were analyzed by quantitative RT-PCR, normalized to GAPDH and U6 snRNA, respectively, using the 2^(− ΔΔCt) method. Granuloma index and developmental phase distribution were assessed histologically.</p> Results <p>IL-22 treatment significantly reduced granuloma index (11.1% reduction, <i>P</i> &lt; 0.05) and systemic TNF-α (16.8% reduction) and IgE (69.8% reduction), while inducing robust upregulation of hepatic STAT3 mRNA (10.4-fold, <i>P</i> &lt; 0.05) and let-7a miRNA (10.6-fold, <i>P</i> &lt; 0.05) with concomitant downregulation of β-catenin transcripts (48.9% reduction from infected levels, <i>P</i> &lt; 0.05). In contrast, PZQ decreased inflammatory mediators and IgE but did not significantly reduce granuloma index and paradoxically increased β-catenin expression (60% elevation from infected levels, <i>P</i> &lt; 0.05). Combination therapy additively suppressed TNF-α (63.8% reduction), IL-17 (35.2% reduction), and IgE (70.2% reduction).</p> Conclusion <p>IL-22 reshapes the hepatic molecular landscape by modulating the STAT3/β-catenin/let-7a signaling axis in <i>S. mansoni</i>-induced granulomas, providing a mechanistic basis for its use as an immunomodulatory adjunct to PZQ rather than as an alternative anthelmintic. These findings identify the STAT3/β-catenin/let-7a circuit as a molecular target for immunotherapeutic intervention in schistosomal hepatic pathology.</p>

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IL-22 modulates STAT3/β-catenin/let-7a signaling and hepatic granulomas in Schistosoma mansoni infection: versus praziquantel and combination treatment

  • 期刊论文

  • 发表日期：

    2026年7月4日

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  • Rasha S. Elbeltagy,
  • Ayatollah A. El-Shorbagy,
  • Rehab E. El-Hennamy,
  • Soad Nady

摘要

Background

Hepatic granuloma formation in Schistosoma mansoni infection is driven by dysregulated cytokine networks and pro-fibrotic signaling pathways, including STAT3, Wnt/β-catenin, and microRNA let-7a circuits. Interleukin-22 (IL-22) is an epithelial-targeted cytokine that signals predominantly through STAT3 and has been implicated in tissue protection and fibrosis modulation. This investigation examined whether IL-22 modulates the STAT3/β-catenin/let-7a molecular axis in schistosomal hepatic granulomas and compared these molecular effects with praziquantel (PZQ) anthelmintic therapy.

Methods

Male mice infected with S. mansoni were treated with recombinant IL-22 (0.36 µg/kg intraperitoneally for 14 days), a single oral dose of praziquantel (PZQ, 600 mg/kg orally), or both. Serum TNF-α, IL-17, IL-22, and IgE were quantified by ELISA. Hepatic STAT3 and β-catenin mRNA and let-7a miRNA expression were analyzed by quantitative RT-PCR, normalized to GAPDH and U6 snRNA, respectively, using the 2^(− ΔΔCt) method. Granuloma index and developmental phase distribution were assessed histologically.

Results

IL-22 treatment significantly reduced granuloma index (11.1% reduction, P < 0.05) and systemic TNF-α (16.8% reduction) and IgE (69.8% reduction), while inducing robust upregulation of hepatic STAT3 mRNA (10.4-fold, P < 0.05) and let-7a miRNA (10.6-fold, P < 0.05) with concomitant downregulation of β-catenin transcripts (48.9% reduction from infected levels, P < 0.05). In contrast, PZQ decreased inflammatory mediators and IgE but did not significantly reduce granuloma index and paradoxically increased β-catenin expression (60% elevation from infected levels, P < 0.05). Combination therapy additively suppressed TNF-α (63.8% reduction), IL-17 (35.2% reduction), and IgE (70.2% reduction).

Conclusion

IL-22 reshapes the hepatic molecular landscape by modulating the STAT3/β-catenin/let-7a signaling axis in S. mansoni-induced granulomas, providing a mechanistic basis for its use as an immunomodulatory adjunct to PZQ rather than as an alternative anthelmintic. These findings identify the STAT3/β-catenin/let-7a circuit as a molecular target for immunotherapeutic intervention in schistosomal hepatic pathology.