GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn’s disease

作者：James A. Sousa, Blanca E. Callejas, Arthur Wang, Eve Higgins, Aydin Herik, Natalie Andonian, Munazza Yousuf, Pina Colarusso, Maitreyi Raman, Derek M. McKay · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-07289-y · 被引用次数：16 · 研究领域：Ferroptosis and cancer prognosis、Biomarkers in Disease Mechanisms、Inflammasome and immune disorders

Abstract Intestinal cell death is a defining feature of Crohn’s disease (CD), a major form of inflammatory bowel disease. The focus on this aspect of enteric inflammation has mainly been on epithelial cells, while other cell types such as stromal and myeloid cells have received less attention. Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by H 2 O 2 . Molecular biology and pharmacological studies ruled out apoptosis and necroptosis, while increased lipid peroxidation and surface expression of the transferrin receptor implicated ferroptosis as the mechanism of the H 2 O 2 -induced cell death: this was supported by suppression of H 2 O 2 -cytotoxicity by liproxstatin-1, a pharmacological inhibitor of ferroptosis. Selenoproteins are important antioxidants, and selenium deficiency can be a feature of CD. Despite normal dietary intake of selenium, monocyte-derived macrophages and intestinal macrophages in individuals with CD had decreased protein and/or mRNA expression of the selenoprotein, glutathione peroxidase (GPx)-1. Knockdown of GPx1 in macrophages from healthy volunteers resulted in increased H 2 O 2 -induced cell death reminiscent of that observed with macrophages from CD. In summary, monocyte-derived macrophages f...