Endoplasmic reticulum stress contributes to ferritin molecules-mediated macrophage migration via P-selectin glycoprotein ligand-1

Scope: Obesity is associated with elevated serum ferritin and increased macrophage activation and infiltration; however, the causal mechanisms underlying this relationship remain undefined. Methods and results: Serum ferritin and soluble P-selectin glycoprotein ligand (sPSGL)-1 level were higher in obese adolescents and patients with moderate nonalcoholic fatty liver disease (NAFLD) compared with controls (all p < 0.05). Multivariate linear regression revealed that serum ferritin was independently associated with sPSGL-1 (B = 0.249, 95% confidence interval: 0.011-0.487, p = 0.041) after adjustment for covariates. The messenger (m) RNA expression of GRP78/Bip, ferritin, and PSGL-1 in leukocytes was greater in patients with nonalcoholic fatty liver disease than in controls. An animal study showed that a tunicamycin injection (an endoplasmic reticulum stress inducer) triggered serum sPSGL-1 and ferritin elevation (all p < 0.01). An in vitro study revealed that serum ferritin and apoferritin induced tumor necrosis factor-α and sPSGL-1 secretion (all p < 0.01). A wound healing assay showed that PSGL-1 blocking inhibited apoferritin-mediated macrophage migration. GRP78/Bip knockdown by the endotoxin EGF-SubA completely inhibited apoferritin-mediated macrophage migration and PSGL-1 expression at the protein and mRNA levels (all p < 0.05). Conclusion: ER stress associated mechanisms are required for apoferritin-/ferritin-mediated macrophage migration via the PSGL-1-dependent pathway.