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mTORC1-Dependent Regulation of the CCL24-CCR3 Axis Controls Granuloma Formation and Maintenance in Sarcoidosis

Xiongjian Rao1,2, Jinpeng Liu2, Derek B Allison2

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.

Biorxiv : the Preprint Server for Biology
|August 12, 2025
PubMed

Insights

This study reveals that mTORC1 pathway hyperactivation drives sarcoidosis-like granulomas in mice. Targeting this pathway and the CCL24-CCR3 axis offers potential therapeutic strategies for sarcoidosis.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Sarcoidosis pathogenesis remains poorly understood, limiting targeted therapy development.
  • Chronic inflammation and immune cell aggregation characterize this granulomatous disease.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving sarcoidosis.
  • To identify novel therapeutic targets for sarcoidosis treatment.

Main Methods:

  • Utilized a Fsp1-Cre mouse model with TSC1/TSC2 deletion to induce sarcoid-like granulomas.
  • Conducted inflammatory cytokine/chemokine array analysis on murine models and human plasma.
  • Investigated the role of mTORC1, STAT3, CCL24, and CCR3 in granuloma formation.

Main Results:

  • mTORC1 pathway hyperactivation in fibroblasts and macrophages induced granuloma formation.
  • CCL24 was identified as a downregulated immunoregulatory molecule in both models and human sarcoidosis patients.
  • mTORC1 was found to suppress CCL24 via STAT3 and promote CCR3 expression, establishing a novel regulatory axis.

Conclusions:

  • A mechanistic link between mTORC1 activation, CCL24-CCR3 dysregulation, and granuloma persistence in sarcoidosis was established.
  • Pharmacological inhibition with rapamycin and azithromycin reduced granuloma burden and normalized the CCL24-CCR3 axis.
  • The identified mTORC1-CCL24-CCR3 axis presents promising therapeutic targets for sarcoidosis intervention.
Keywords:
CCL24-CCR3inflammationmTORsarcoidosis

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