CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway

Abstract

CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-β1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of SLC7A11 and GPX4. These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when CXCR2 was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate SLC7A11 and GPX4 expression, protecting endothelial cells from ferroptosis.

Apoptotic Bodies Derived from Fibroblast‐Like Cells in Subcutaneous Connective Tissue Inhibit Ferroptosis in Ischaemic Flaps via the miR‐339‐5p/KEAP1/Nrf2 Axis

“…[ 13 ] Therefore, it is necessary to determine whether ferroptosis was regulated by ABs through SLC7A11 modulation in flaps. Relevant literatures indicated that erastin inhibited SLC7A11 protein levels in endothelial cells [ 31 ] and macrophage cells. [ 32 ] Therefore, erastin was used as an SLC7A11 inhibitor in the flap model.…”

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

“…Studies suggest CXCL8 can accelerate tumor cell proliferation, epithelial–mesenchymal transition (EMT), angiogenesis, and impede anti-tumor immunity ( Ravi et al, 2023 ). CXCL3, a bioactive protein of low molecular weight, primarily recruits and activates various cells expressing the CXC chemokine receptor (CXCR)12, which is involved in cell migration, invasion, and angiogenesis and plays a crucial role in the development of cardiovascular and pulmonary diseases ( Chang et al, 2023 ; Ji et al, 2023 ). Research also reveals that SPP1 impacts the tumor microenvironment by promoting inflammatory responses, immune suppression, and regulating extracellular matrix (ECM) remodeling to support tumor growth ( Lv et al, 2023 ; Yu et al, 2023 ).…”

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

“…Nuclear factor-κB (NF-κB) is a transcription factor found in all animal cell types that plays a crucial role in immune and inflammatory responses [120]. As such, researchers have focused on understanding the NF-κB-related pathway, which presents a promising target for addressing a variety of pathological processes such as tumor progression, injury, and inflammation [121][122][123]. The NF-κB pathway has been implicated in regulating neuroinflammation following central nervous system diseases, making it a particularly important area of study [124].…”