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Review
. 2024 Jul 9;25(14):7527.
doi: 10.3390/ijms25147527.

Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy

Mateusz Wątroba  1 , Anna D Grabowska  1 , Dariusz Szukiewicz  1
Affiliations
Review

Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy

Mateusz Wątroba et al. Int J Mol Sci. .

Abstract

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron-microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.

Keywords: CX3CL1/CX3CR1 axis; advanced glycation end products; central nervous system; chemokine CX3CL1; diabetes mellitus; diabetic encephalopathy; fractalkine; hyperglycemia; neuroinflammation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic structure of the C-X3-C motif chemokine ligand 1 (CX3CL1), also known as fractalkine or neurotactin. Both forms of the chemokine are shown: membrane-bound (transmembrane) CX3CL1 and soluble CX3CL1. The soluble CX3CL1, containing an N-terminal chemokine domain and an extracellular mucin-like stalk, is generated through the cleavage of the membrane-bound molecule near the outer surface of the membrane (marked symbolically with scissors and crossed red lines). Release of soluble CX3CL1 may occur upon exposure to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), tumor necrosis factor alpha (TNF-α) converting enzyme (TACE or ADAM17), matrix metalloproteinase-2 (MMP-2), or cathepsins (CTS). Adapted from [63].
Figure 2
Figure 2
Downstream signaling pathways (A–D) after the activation of the CX3C motif chemokine receptor 1 (CX3CR1) caused by the attachment of the only endogenous ligand, chemokine CX3CL1 (fractalkine), released in a soluble form (sCX3CL1) from neurons. Gene transcription changes are a consequence of the signal transducer and activator of the transcription protein (STAT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cAMP/Ca2+ response element binding protein (CREB) activation, while inhibiting the members of the class O of forkhead box transcription factors (FOXO). To keep the figure clear, the interaction of CX3CR1 with other receptors has been omitted.
Figure 3
Figure 3
The importance of microglia and CX3CL1/CX3CR1 signaling in the vicious cycle of microglia–neuron interaction during neuroinflammation in diabetic encephalopathy. Microglia activation in diabetic encephalopathy occurs as a result of the action of signaling pathways related to the following: ❶ pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), triggering receptor expressed on myeloid cells 2/DNAX-activating protein of 12 kDa (TRM2/DAP12), and advanced glycation end product/receptor for advanced glycation end product (AGE-RAGE), ❷ the activation of p38 mitogen-activated protein kinases, a class of mitogen-activated protein kinases (MAPKs) p38 MAPK, and ❸ purinergic signaling. Microglial inflammation may also develop as a consequence of blocking the interaction of the immunomodulatory protein CD200 with its receptor CD200R (marked with crossed out red lines) ❹, because the CD200/CD200R signaling provides immunosuppression due to the inhibition of macrophages, the induction of regulatory T cells, the switching of cytokine profiles from T helper-1 (Th1) to T helper-2 (Th2), the inhibition of tumor-specific T cell immunity, and the induction of myeloid-derived suppressor cells (MDSCs) [149]. Neuronal hyperactivity in diabetic encephalopathy may be caused by both neurotoxic factors outside microglia and an inflammatory response within microglia. Neurotoxic agents increase the risk of cognitive deficits due to impaired synaptic plasticity. Whatever the cause, neuronal hyperactivity has a feedback-activating effect on microglia by releasing slow-acting microglial activators, such as matrix metalloproteinase-9 (MMP-9), adenosine triphosphate (ATP), monocyte chemoattractant protein-1 (MCP-1), and fractalkine (CX3CL1) ❺. The soluble form of CX3CL1 (sCX3CL1) has a pro-inflammatory effect by stimulating metabotropic CX3CR1 receptors expressed in microglial cells ❻.
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