Modulatory Effects of Fractalkine on Inflammatory Response and Iron Metabolism of Lipopolysaccharide and Lipoteichoic Acid-Activated THP-1 Macrophages

Abstract

Fractalkine (CX3CL1) acts as a chemokine as well as a regulator of iron metabolism. Fractalkine binds CX3CR1, the fractalkine receptor on the surface of monocytes/macrophages regulating different intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), phospholipase C (PLC) and NFκB contributing to the production of pro-inflammatory cytokine synthesis, and the regulation of cell growth, differentiation, proliferation and metabolism. In this study, we focused on the modulatory effects of fractalkine on the immune response and on the iron metabolism of Escherichia coli and Pseudomonas aeruginosa lipopolysaccharides (LPS) and Staphylococcus aureus lipoteichoic acid (LTA) activated THP-1 cells to get a deeper insight into the role of soluble fractalkine in the regulation of the innate immune system. Pro-inflammatory cytokine secretions of the fractalkine-treated, LPS/LTA-treated, and co-treated THP-1 cells were determined using ELISArray and ELISA measurements. We analysed the protein expression levels of signalling molecules regulated by CX3CR1 as well as hepcidin, the major iron regulatory hormone, the iron transporters, the iron storage proteins and mitochondrial iron utilization. The results showed that fractalkine treatment alone did not affect the pro-inflammatory cytokine secretion, but it was proposed to act as a regulator of the iron metabolism of THP-1 cells. In the case of two different LPS and one type of LTA with fractalkine co-treatments, fractalkine was able to alter the levels of signalling proteins (NFκB, PSTAT3, Nrf2/Keap-1) regulating the expression of pro-inflammatory cytokines as well as hepcidin, and the iron storage and utilization of the THP-1 cells.

The role of the CX3CL1/CX3CR1 axis as potential inflammatory biomarkers in subjects with periodontitis and rheumatoid arthritis: A systematic review

“…Both molecular forms of the protein can be induced by pro-inflammatory cytokines such as IL-1β, TNF-α, interferon-γ (IFN-γ), as well as virulence factors such as LPS from bacteria like P. gingivalis and even oxygen tension. 14,16,17,42 The CX3CR1 is the only member of the heterotrimeric G-protein-coupled transmembrane receptor superfamily of receptors. It is primarily expressed in monocytes/macrophages, osteoclasts, gingival fibroblasts, natural killer cells, and cytotoxic T lymphocytes.…”

“…On the other hand, it can also present as a soluble protein (sCX3CL1); this molecular form of the protein is produced by proteolysis due to the participation of different enzymes such as TNF‐α‐converting enzyme/disintegrin‐like metalloproteinase 17 (ADAM17), disintegrin domain‐containing protein and metalloproteinase 10 (ADAM 10), matrix metalloproteinase 3 (MMP‐3) and cathepsin S that cleave the transmembrane domain giving rise to a potent chemoattractant for leukocytes. Both molecular forms of the protein can be induced by pro‐inflammatory cytokines such as IL‐1β, TNF‐α, interferon‐γ (IFN‐γ), as well as virulence factors such as LPS from bacteria like P. gingivalis and even oxygen tension 14,16,17,42 …”

Potential Impact of Prosthetic Biomaterials on the Periodontium: A Comprehensive Review

“…After cleavage of the signal peptide sequence, the synthesized polypeptide is glycosylated and then incorporated into the cell membrane constituting a type I transmembrane glycoprotein of 373 amino acids and with a molecular weight of 100 kDa [ 157 , 164 ]. The membrane-bound form has an important function as a cell adhesion molecule and can be induced by proinflammatory cytokines such as interferon-γ (IFN- γ), TNF-α [ 164 ] and interleukin 1-β [ 121 ] as well as virulence factors such as LPS [ 165 ]. This function results from the interaction between the functional chemokine domain present in the extracellular region of the protein with the N-terminal end of the fractalkine receptor (CX3CR1) [ 163 ], which is expressed by NK cells, cytotoxic T lymphocytes, monocytes/macrophages, osteoclasts and gingival fibroblasts [ 162 ].…”

Regulation of iron metabolism in HEC‐1A endometrium cells by macrophage‐derived factors and fractalkine

“…Moreover, iron availability acts as a regulatory factor of endometrial receptivity as well as embryo implantation. Recent findings underlie the importance of iron in the expression of receptivity‐related genes (Pandur et al, 2023).…”

“…Recent studies revealed that FKN might contribute to endometrial receptivity, implantation, and pregnancy (Kervancioglu Demirci et al, 2016; Machairiotis et al, 2021; Pap et al, 2020; Toprak Sager et al, 2022). It has also been described that FKN can modulate the inflammatory action of macrophages by altering the production of proinflammatory cytokines (Gong et al, 2021; Pandur et al, 2022).…”