Ferritin-mediated neutrophil extracellular traps formation and cytokine storm via macrophage scavenger receptor in sepsis-associated lung injury.

BACKGROUND: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear. METHODS: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4-/-, Elane-/- and Cybb-/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways. RESULTS: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury. CONCLUSIONS: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract.

In Situ Metal-Oxygen-Hydrogen Modified B-Tio2 @Co2 P-X S-Scheme Heterojunction Effectively Enhanced Charge Separation for Photo-assisted Uranium Reduction.

Photo-assisted uranium reduction from uranium mine wastewater is expected to overcome the competition between impurity ions and U(VI) in the traditional process. Here, B-TiO2 @Co2 P-X S-scheme heterojunction with metal-oxygen-hydrogen (M-O-H) is developed insitu modification for photo-assisted U(VI) (hexavalent uranium) reduction. Relying on the DFT calculation and Hard-Soft-Acid-Base (HSAB) theory, the introduction of metal-oxygen-hydrogen (M-O-H, hard base) metallic bonds in the B-TiO2 @Co2 P-X is found to enhance the hydrophilicity and the capture capability for uranyl ion (hard acid). Accordingly, B-TiO2 @Co2 P-500 hybrid nanosheets exhibit excellent U(VI) reduction ability (>98%) in the presence of competing ions. By self-consistent energy band calculations and in-situ KPFM spectral analysis, the formation of the internal electric field between B-TiO2 and Co2 P at the heterojunction is proven, offering a strong driving force and atomic transportation highway for accelerating the S-scheme charge carriers directed migration and promoting the photocatalytic reduction of uranium. This work provides a valuable route to explore the functionally modified photocatalyst with high-efficiency photoelectron separation for U(VI) reduction.

Unveiling the Critical Role of Surface Hydroxyl Groups for Electro-Assisted Uranium Extraction from Wastewater.

The electro-driven extraction of uranium from fluorine-containing uranium wastewater is anticipated to address the challenge of separating fluoro-uranium complexes in conventional technologies. Herein, we developed hydroxy-rich cobalt-based oxides (CoOx) for electro-assisted uranium extraction from fluorine-containing wastewater. Relying on theoretical calculations and other spectral measurements, the hydroxy-rich CoOx nanosheets can enhance the affinity for uranium due to the existence of a substantial quantity of hydroxyl groups. Accordingly, the CoOx nanosheets exhibit outstanding U(VI) removal efficiency in the presence of fluorine ions. Through the utilization of X-ray absorption fine structure (XAFS), we confirm that hydroxy-rich CoOx nanosheets capture free uranyl ions to form a sturdy 2Oax-1U-3Oeq configuration, which can be achieved through electro-driven fluorine-uranium separation. Notably, for the first time, the whole reaction process of uranium species on the CoOx surface from the initial uranium single atom growth to uranium oxide nanosheets is monitored by aberration-corrected transmission electron microscopes (AC-TEM). This work provides a paradigm for the advancement of novel functional materials as electrocatalysts for uranium extraction, as well as a new approach for studying the evolution mechanism of uranium species.

METTL3-mediated N6-methyladenosine exacerbates ferroptosis via m6A-IGF2BP2-dependent mitochondrial metabolic reprogramming in sepsis-induced acute lung injury.

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis-induced acute lung injury (SI-ALI). We demonstrate that NETs induce SI-ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI-ALI is accompanied by upregulation of ferroptosis depending on METTL3-induced m6A modification of hypoxia-inducible factor-1α (HIF-1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI-ALI caused by NETs in a caecum ligation and puncture (CLP)-induced SI-ALI model using METTL3 condition knockout (CKO) mice and wild-type mice. Our results indicate the crucial role of NETs in the progression of SI-ALI via NET-activated METTL3 m6A-IGF2BP2-dependent m6A modification of HIF-1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.

Neutrophil extracellular traps-triggered impaired autophagic flux via METTL3 underlies sepsis-associated acute lung injury.

Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.