Endoplasmic reticulum stress contributes to ferritin molecules-mediated macrophage migration via P-selectin glycoprotein ligand-1.
Obesity is associated with elevated serum ferritin and increased macrophage activation and infiltration; however, the causal mechanisms underlying this relationship remain undefined.



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).



ER stress associated mechanisms are required for apoferritin-/ferritin-mediated macrophage migration via the PSGL-1-dependent pathway.
Department of Nutrition, MacKay Memorial Hospital, Taiwan.
Chi-Mei
CM
Wang
School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan.|Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Yue-Hwa
YH
Chen
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Yu-Chieh
YC
Lee
School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan.|Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Jung-Su
JS
Chang
D000818:Animals; D001052:Apoferritins / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005293:Ferritins / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D006360:Heat-Shock Proteins; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy; D009765:Obesity; D019007:P-Selectin / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014415:Tunicamycin; D005293:Ferritins; D001052:Apoferritins
Apoferritin, Endoplasmic reticulum stress; Macrophage; Obesity; P-selectin glycoprotein-1; Serum ferritin