Abstract
Fractalkine (CX3CL1) is a potent inflammatory mediator of the central nervous system, which is expressed by neurons and regulates microglial functions by binding to fractalkine receptor (CX3CR1). It has been demonstrated that neuroinflammation plays an important role in iron accumulation of the brain leading to neuronal cell death. The major regulator of iron homeostasis is the peptide hormone hepcidin. Hepcidin expression is triggered by inflammatory conditions, which may contribute to the neuronal iron accumulation. In the present study, we established a bilaminar co-culture system of differentiated SH-SY5Y cells and BV-2 microglia as a neuronal model to examine the effect of soluble fractalkine on iron homeostasis of microglia and SH-SY5Y cells. We determined the hepcidin expression of fractalkine-treated microglia which showed significant elevation. We examined the relation between increased hepcidin secretion, the known hepcidin regulators and the signalling pathways controlled by fractalkine receptor. Our data revealed that TMPRSS6 and alpha 1-antitrypsin levels decreased due to fractalkine treatment, as well as the activity of NFκB pathway and the tyrosine phosphorylation of STAT5 factor. Moreover, fractalkine-induced hepcidin production of microglia initiated ferroportin internalisation of SH-SY5Y cells, which contributed to iron accumulation of neurons. Our results demonstrate that soluble form of fractalkine regulates hepcidin expression of BV-2 cells through fractalkine-mediated CX3CR1 internalisation. Moreover, fractalkine indirectly contributes to the iron accumulation of SH-SY5Y cells by activating ferroportin internalisation and by triggering the expressions of divalent metal transporter-1, ferritin heavy chain and mitochondrial ferritin.
Highlights
Fractalkine or CX3CL1 belongs to the δ subfamily of chemokines (Harrison et al 1998; Rostene and Buckingham 2007)
Fractalkine exists in two different forms: a membrane-bound glycoprotein providing direct interaction with its sole receptor, CX3CR1, which is found exclusively on microglia; and a soluble form produced by proteolytic cleavage of the N-terminal chemokine domain of the membrane-bound
We described a new regulatory pathway of hepcidin expression mediated by fractalkine in BV-2 microglial cells and investigated the effect of microglial hepcidin on the iron metabolism of differentiated SH-SY5Y cells using a bilaminar co-culture system
Summary
Fractalkine or CX3CL1 belongs to the δ subfamily of chemokines (Harrison et al 1998; Rostene and Buckingham 2007). It is a unique chemokine, which is constitutively expressed by neurons (Neiva et al 2014). Iron is an essential element required for many different biological processes: regulation of oxygen transport, cellular metabolism, DNA synthesis, growth and development, neurotransmission, myelination, and neuronal metabolism (Ward et al 2014; Sangkhae and Nemeth 2017). The cooperation of many positive and negative transcriptional regulators maintains the balance of hepcidin synthesis (De Domenico et al 2007; Muckenthaler 2008; Rishi et al 2015)
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