Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin

Abstract

Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major components. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2′-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.

Ferroptotic cardiomyocyte-derived exosomes promote cardiac macrophage M1 polarization during myocardial infarction

“… Dai et al (2020) demonstrated for the first time a link between ferroptotic cells and macrophages, that is, exosomes released by ferroptotic pancreatic cancer cells carry KRAS protein to macrophages, resulting in the M2 polarization of macrophages. Ito et al (2021) first evidenced that ferroptosis-dependent EVs from macrophage by loading ferritin contribute to mesothelial carcinogenesis ( Ito et al, 2021 ). These results led us to wonder whether ferroptotic cardiomyocytes acted on macrophages function change through exosomes.…”

Iron as spirit of life to share under monopoly

“…FedEVs contain a high amount of iron-loaded ferritin and of note are taken up by the mesothelial cells present at the surface of somatic cavities, eventually causing oxidative DNA damage. (110) Thus, iron sharing system may lead to harmful effects under the situation of monopoly, where the individual tries not to release any subtle amount of iron to the other infected species or their equivalents. (111)…”

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

“…Ferritin is composed of ferritin heavy polypeptide 1 (FTH1) and ferritin light polypeptide 1, and functions as the major iron sequestration and storage protein to decrease intracellular iron concentrations. In contrast, ferritin proteolytic degradation leads to rapid releases of iron, and subsequently increases intracellular iron levels and ferroptosis [ [13] , [14] , [15] ]. Nuclear receptor coactivator 4 (NCOA4) is identified as a cargo receptor for the autophagic degradation of ferritin that is known as ferritinophagy, and NCOA4-mediated ferritin turnover contributes to the elevation of intracellular iron levels and subsequent ferroptosis in different cell types, including the glioblastoma cells [ 16 , 17 ].…”