Mechanism of SLC15A3 Regulating Macrophage Oxidative Stress in the Pathogenesis of Traumatic Tracheal Stenosis

Studies have shown that upregulation of Solute carrier family 15 member 3 (SLC15A3, PHT2) on the surface of macrophages can suppress the activation of the Sequestosome 1 (p62)-Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant stress pathway, thereby facilitating the progression of pulmonary fibrosis. However, the association between SLC15A3 and traumatic tracheal stenosis (TS)-hereafter referred to as TS-remains unclear.

This study detected and analyzed relevant indicators via three approaches: clinical specimens were used to assess target indicators; for in vitro experiments, human THP-1 cells were induced to differentiate into M2 macrophages using phorbol 12-myristate 13-acetate (PMA) combined with interleukin-4 (IL-4) and interleukin-13 (IL-13), and after inducing oxidative stress with hydrogen peroxide (H₂O₂), the M2 macrophages were co-cultured with tracheal fibroblasts; for in vivo experiments, Sprague-Dawley (SD) rats were randomly divided into four groups (Control, TS, Sh-NC+TS, and Sh-SLC15A3+TS), and the TS model was established by scraping the tracheal mucosa with a nylon brush to induce traumatic injury.

Experimental analyses detected M2 macrophage accumulation in TS patients. We observed elevated expression of SLC15A3, collagen type I alpha 1 (COL1A1) and α-smooth muscle actin (α-SMA), alongside reduced levels of the antioxidant molecules p62, Nrf2 and superoxide dismutase 2 (SOD2). In vitro and in vivo data indicate a possible association between SLC15A3 knockdown, altered p62-Nrf2 pathway activity, attenuated inflammation and relieved tissue fibrosis, which might be relevant to alleviated airway stenosis severity.

This study clarifies the regulatory role of SLC15A3 in the pathogenesis of TS, providing a novel potential therapeutic target for inhibiting tracheal fibrosis in clinical practice.