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<p>Thiazolidine derivatives exert anti-inflammatory effects by inhibiting the NF-κB pathway and promoting macrophage polarization toward the anti-inflammatory M2 phenotype, partially through PPARγ activation. Our previous work identified thiazolidine derivative <b>13</b> [methyl 2-(benzoylimino)-3-methyl-4-(4-nitrobenzyl)-1,3-thiazolidine-4-carboxylate] as a potent immunomodulator that reduces pro-inflammatory mediators and enhances anti-inflammatory markers. However, its direct interaction with PPARγ remains unclear. This study aims to evaluate whether thiazolidine <b>13</b> activates PPARγ and contributes to M2 macrophage polarization using LPS-stimulated RAW 264.7 cells, cell transactivation assay and reporter gene (Hella cells), LPS-stimulated THP-1 cells, and molecular docking analysis. <b>Compound 13</b> reduced NO₂⁻ production, CD80 expression, and pro-inflammatory cytokines while increasing IL-10, TGF-β, and CD206 in LPS-stimulated RAW 264.7 macrophages. <b>Compound 13</b> also inhibited NO production in LPS-stimulated THP-1 cells. These effects were only partially reversed by PPARγ antagonists, suggesting additional PPARγ-independent mechanisms, while the induction of CD206 was closely linked to partial PPARγ activation. Docking studies supported this profile, showing that the (<i>S</i>) enantiomer of thiazolidine <b>13</b> adopts a binding mode typical of partial PPARγ agonists and exhibits a higher predicted affinity than the (<i>R</i>) enantiomer. <b>Compound 13</b> acts as a partial PPARγ modulator capable of shifting macrophages from a pro-inflammatory toward an anti-inflammatory phenotype (M2-like). This dual action relies on the inhibition of NF-κB signaling and partial PPARγ activation. The predominance of the M2-like subpopulation, underscores its role in resolving inflammation and promoting tissue repair.</p> Graphical abstract <p></p>

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The anti‑inflammatory activity of 2‑iminothiazolidines: the role of PPARγ and M2 macrophage subpopulations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Eduarda Talita Bramorski Mohr,
  • Tainá Larissa Lubschinski,
  • Pedro Augusto Marocco Moro,
  • Larissa Benvenutti,
  • Natáli Tereza Capistrano Costa,
  • Pedro Luís Pereira Braga de Sousa,
  • Marcus Mandolesi Sá,
  • Marcelo Zaldini Hernandes,
  • Flora Aparecida Milton,
  • José Roberto Santin,
  • Eduardo Monguilhott Dalmarco

摘要

Thiazolidine derivatives exert anti-inflammatory effects by inhibiting the NF-κB pathway and promoting macrophage polarization toward the anti-inflammatory M2 phenotype, partially through PPARγ activation. Our previous work identified thiazolidine derivative 13 [methyl 2-(benzoylimino)-3-methyl-4-(4-nitrobenzyl)-1,3-thiazolidine-4-carboxylate] as a potent immunomodulator that reduces pro-inflammatory mediators and enhances anti-inflammatory markers. However, its direct interaction with PPARγ remains unclear. This study aims to evaluate whether thiazolidine 13 activates PPARγ and contributes to M2 macrophage polarization using LPS-stimulated RAW 264.7 cells, cell transactivation assay and reporter gene (Hella cells), LPS-stimulated THP-1 cells, and molecular docking analysis. Compound 13 reduced NO₂⁻ production, CD80 expression, and pro-inflammatory cytokines while increasing IL-10, TGF-β, and CD206 in LPS-stimulated RAW 264.7 macrophages. Compound 13 also inhibited NO production in LPS-stimulated THP-1 cells. These effects were only partially reversed by PPARγ antagonists, suggesting additional PPARγ-independent mechanisms, while the induction of CD206 was closely linked to partial PPARγ activation. Docking studies supported this profile, showing that the (S) enantiomer of thiazolidine 13 adopts a binding mode typical of partial PPARγ agonists and exhibits a higher predicted affinity than the (R) enantiomer. Compound 13 acts as a partial PPARγ modulator capable of shifting macrophages from a pro-inflammatory toward an anti-inflammatory phenotype (M2-like). This dual action relies on the inhibition of NF-κB signaling and partial PPARγ activation. The predominance of the M2-like subpopulation, underscores its role in resolving inflammation and promoting tissue repair.

Graphical abstract