JTE-013 reduces inflammation and improves pulmonary fibrosis by regulating the TRAF2/NF - κB/IGF-1 signaling pathway and macrophage polarization

After exposure to pathological stimuli, macrophages play a crucial role in the immune regulation of early pulmonary inflammation. Emerging evidence suggests that macrophage-mediated responses are closely associated with the development of pulmonary fibrosis, a condition characterized by excessive extracellular matrix deposition and architectural distortion of lung tissue. Sphingosine-1-phosphate (S1P) has been implicated in inflammatory processes, and clinical observations indicate that S1P levels correlate with disease severity in pulmonary fibrosis. However, the specific mechanisms through which S1P signaling modulates macrophage function in this context remain incompletely understood. We investigated the effects of JTE-013, a selective S1PR2 Antagonist, on macrophage polarization and its therapeutic potential in pulmonary fibrosis. We established a bleomycin-induced murine model that recapitulates key features of inflammatory and fibrotic phases of lung injury. Complementary in vitro experiments were performed using S1P-stimulated macrophage cultures to examine polarization patterns. Our findings indicate that JTE-013 treatment attenuates inflammatory responses by modulating S1P-S1PR2 signaling and downstream TRAF2/NF-κB activation, resulting in reduced M1 macrophage polarization and decreased production of pro-inflammatory cytokines including TNF-α. JTE-013 administration was associated with suppressed IGF-1 signaling, diminished M2 polarization, and reduced expression of pro-fibrotic mediators. These changes were accompanied by decreased extracellular matrix deposition, as evidenced by reduced α-SMA expression, and amelioration of tissue remodeling. Collectively, our results suggest that JTE-013 may alleviate pulmonary fibrosis progression by modulating S1P-S1PR2 signaling, influencing macrophage polarization balance, and attenuating aberrant extracellular matrix accumulation. These findings provide new insights into the potential therapeutic targeting of S1PR2 in macrophage-mediated fibrotic lung diseases.

JTE-013; Macrophage polarization; Pulmonary fibrosis; Pulmonary inflammation; S1P.