Corrigendum: PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip.

[This corrects the article DOI: 10.3389/fimmu.2022.731500.].

PHLDA1 Suppresses TLR4-Triggered Proinflammatory Cytokine Production by Interaction With Tollip.

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) has been reported to be expressed in many mammalian tissues and cells. However, the functions and exact mechanisms of PHLDA1 remain unclear. In this study, we found that PHLDA1 expression was significantly altered in macrophages after exposure to lipopolysaccharide (LPS) in vitro, suggesting that PHLDA1 may be involved in the regulation of TLR4 signaling pathway activated by LPS. PHLDA1 attenuated the production of LPS-stimulated proinflammatory cytokines (TNF-α, IL-6, and IL-1ß). Further research showed that the phosphorylation levels of some important signal molecules in TLR4/MyD88-mediated MAPK and NF-κB signaling pathways were reduced by PHLDA1, which in turn impaired the transcription factors NF-κB and AP1 nuclear translocation and their responsive element activities. Furthermore, we found that PHLDA1 repressed LPS-induced proinflammatory cytokine production via binding to Tollip which restrained TLR4 signaling pathway. A mouse model of endotoxemia was established to confirm the above similar results. In brief, our findings demonstrate that PHLDA1 is a negative regulator of LPS-induced proinflammatory cytokine production by Tollip, suggesting that PHLDA1 plays an anti-inflammatory role through inhibiting the TLR4/MyD88 signaling pathway with the help of Tollip. PHLDA1 may be a novel therapeutic target in treating endotoxemia.

Current insights into the expression and functions of tumor-derived immunoglobulins.

Numerous studies have reported expressions of immunoglobulins (Igs) in many human tumor tissues and cells. Tumor-derived Igs have displayed multiple significant functions which are different from classical Igs produced by B lymphocytes and plasma cells. This review will concentrate on major progress in expressions, functions, and mechanisms of tumor-derived Igs, similarities and differences between tumor-derived Igs and B-cell-derived Igs. We also discuss the future research directions of tumor-derived Igs, including their structural characteristics, physicochemical properties, mechanisms for rearrangement and expression regulation, signaling pathways involved, and clinical applications.

Exosomes containing miR-122-5p secreted by LPS-induced neutrophils regulate the apoptosis and permeability of brain microvascular endothelial cells by targeting OCLN.

OBJECTIVE: To explore the effect of exosomes containing miR-122-5p secreted by lipopolysaccharide (LPS)-induced neutrophils on the apoptosis and permeability of brain microvascular endothelial cells (BMECs). METHODS: Neutrophils in blood were isolated, purified and identified. LPS-induced neutrophils were co-cultured with BMECs. Untreated or LPS-induced neutrophil exosomes were isolated and identified with a transmission electron microscope. miR-122-5p expressions in the exosomes were detected by real-time quantitative polymerase chain reaction, and then the exosomes were co-cultured with BMECs. Bioinformatics analysis was performed to predict the downstream target gene of miR-122-5p, and OCLN was selected as the subject. Dual luciferase reporter assay was carried out to verify the interactive relationship between OCLN and miR-122-5p. LPS and miR-122-5p were used to treat neutrophils, and then exosomes were collected. Exosome or OCLN was embedded in BMECs. The proliferation, colony forming ability and apoptosis of BMECs were detected by cholecystokinin octopeptide, clone formation assay and flow cytometry, respectively. Corresponding kits were used to detect the activities of reactive oxygen species, superoxide dismutase, malondialdehyde and catalase. Vascular endothelial growth factor and tight junction proteins (ZO-1 and Claudin-5) expressions were measured by Western blot for cell permeability evaluation. RESULTS: miR-122-5p had an increased expression in LPS-induced neutrophil exosomes and could promote oxidative stress, apoptosis and permeability increase of BMECs and the inhibition of BMECs proliferation and colony formation (P<0.05). miR-122-5p targeted the binding with OCLN and down-regulated OCLN expression. OCLN overexpression partly decreased the malignant effect of miR-122-5p on BMECs (P<0.05). CONCLUSION: LPS can induce neutrophils to secrete exosomes containing miR-122-5p. The down-regulation of OLCN expression can aggravate BMECs injury.

MicroRNA miR-126 attenuates brain injury in septic rats via NF-κB signaling pathway.

The purpose of this study was to investigate the impact and mechanism of microRNA miR-126 on brain injury induced by blood-brain barrier (BBB) damage in septic rats. We used cecal ligation and perforation (CLP) to create a rat model of sepsis. The experimental rats were randomly divided into Control group, CLP group, CLP + miR-NC group, CLP + miR-126 group and CLP + miR-126 + NF-κB pathway agonist (PMA) group. MiR-126 expressed in the brain tissue of CLP rats was down-regulated by qRT-PCR. Upregulation of miR-126 in CLP rats could improve brain injury and BBB marker protein level, reduce brain water content, Evans blue extravasation, inflammation, and excessive oxidative stress. This could also result in an inhibition of NF-κB signaling pathway activity. In conclusion, miR-126 overexpression can prevent brain injury caused by BBB damage via the inhibition of NF-κB signaling pathway activity.