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Review
. 2023 Sep 25:16:1249320.
doi: 10.3389/fnmol.2023.1249320. eCollection 2023.

Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases

Jaime Eugenín  1 , Laura Eugenín-von Bernhardi  2 , Rommy von Bernhardi  3
Affiliations
Review

Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases

Jaime Eugenín et al. Front Mol Neurosci. .

Abstract

The chemokine fractalkine (FKN, CX3CL1), a member of the CX3C subfamily, contributes to neuron-glia interaction and the regulation of microglial cell activation. Fractalkine is expressed by neurons as a membrane-bound protein (mCX3CL1) that can be cleaved by extracellular proteases generating several sCX3CL1 forms. sCX3CL1, containing the chemokine domain, and mCX3CL1 have high affinity by their unique receptor (CX3CR1) which, physiologically, is only found in microglia, a resident immune cell of the CNS. The activation of CX3CR1contributes to survival and maturation of the neural network during development, glutamatergic synaptic transmission, synaptic plasticity, cognition, neuropathic pain, and inflammatory regulation in the adult brain. Indeed, the various CX3CL1 forms appear in some cases to serve an anti-inflammatory role of microglia, whereas in others, they have a pro-inflammatory role, aggravating neurological disorders. In the last decade, evidence points to the fact that sCX3CL1 and mCX3CL1 exhibit selective and differential effects on their targets. Thus, the balance in their level and activity will impact on neuron-microglia interaction. This review is focused on the description of factors determining the emergence of distinct fractalkine forms, their age-dependent changes, and how they contribute to neuroinflammation and neurodegenerative diseases. Changes in the balance among various fractalkine forms may be one of the mechanisms on which converge aging, chronic CNS inflammation, and neurodegeneration.

Keywords: Alzheimer’s disease; CX3CL1; CX3CR1; Parkinson’s disease; aging; metalloproteases; neurodegenerative disease; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Membrane-bound and soluble fractalkine. Fractalkine (CX3CL1) is synthesized in neurons as a precursor that is rapidly transported to the cell surface, where it is incorporated as a transmembrane protein (mCX3CL1, native). We illustrate the mCX3CL1 molecule indicating its chemokine, mucine-like stalk, transmembrane, and cytoplasmic domains. At the cellular surface, mCX3CL1 is targeted for metalloproteinase-dependent cleavage that releases soluble fractalkine (sCX3CL1) containing most of the mucine-like stalk and the chemokine domain. Key proteases contributing to CX3CL1 cleavage include TNFα converting enzyme (TACE; ADAM17), ADAM10, and cathepsin S. Physiological CX3CL1 cleavage occurs at different sites depending on the protease. sCX3CL1 forms do not differ much in their functional effects. Both CX3CL1 types, mCX3C1L and sCX3CL1, bind the CX3CR1 located in microglia. A CX3CL1 form restricted to the chemokine domain (cdCX3CL1) has been artificially generated.
Figure 2
Figure 2
Inflammation associated signaling activated by fractalkine. The activation of the CX3CL1/CX3CR1 axis activates the mitogen-activated protein kinases (MAPKs) including the extracellular signal-regulated kinases (ERK), p38-MAPK, and c-Jun NH(2)-terminal kinase (JNK). MAPKS activate the stress-activated protein kinase-1 (MSK1), and consequently, activate NFκB pathway, and therefore, the production and release of inflammatory mediators. By contrast, the activation of the AKT/ERK signaling pathway induces factor 2 related to nuclear factor E2 (Nrf2) to be translocated into the nucleus leading to increased transcription of various antioxidant and cytoprotective genes such as antioxidant response element (ARE) and heme oxygenase-1 (HO-1), which increase the phagocytic and anti-inflammatory capacity of microglia. To summarize, activation of CX3CL1/CX3CR1 axis increases NFκB (Galan-Ganga et al., 2019; Liu et al., 2019), promotes release of pro-inflammatory cytokines by microglia, and enhances the Nrf2 activation that increases anti-oxidant and anti-inflammatory response (Lastres-Becker et al., 2014; Castro-Sanchez et al., 2019; Li et al., 2019; Trougakos, 2019). Akt, protein kinase B; ERK, extracellular signal-regulated kinases; GSK-3β, glycogen synthase kinase-3β; HO-1, heme oxygenase 1; IKB, Ikappa B protein; IKK, IkappaB kinase; IL1β, interleukin-1β; JNK, c-Jun N-terminal kinase; KEAP-1, Kelch-like ECH associating protein-1; MEK, mitogen-activated protein kinase kinase; MEKK, MEK kinase or mitogen activated protein (MAP) kinase kinase kinase; MSK-1, mitogen- and stress-activated kinase 1; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor erythroid 2-related factor 2; NRF2/KEAP-1, nuclear factor erythroid 2-related factor 2/Kelch-like ECH associating protein-1;NO, nitric oxide; pAkt, phosphorylated AKT; pGSK-3β, phosphorylated glycogen synthase kinase-3β; PDK1, protein 3-phosphoinositide-dependent protein kinase-1; PI3K, phosphoinositide 3-kinase, also called phosphatidylinositol 3-kinase; PKC, protein kinase-C; PLC, phospholipase C p38MAPK, p38 mitogen-activated protein kinase; Ras, rat sarcoma virus small-GTPase; TNFα, tumor necrosis factor-α.
Figure 3
Figure 3
Differential functions of the various Fractalkine forms. Scheme illustrating different processes triggered by the activation of microglia by CX3CR1 binding mCX3CL1, sCX3CL1, and cdCX3CL1. Newly reported CX3CL1-ICD proposed functions are included. Within sCX3CL1s, we considered fragments resulting from ectodomain shedding or recombinant synthesis based on the action of proteases. Note that cdCX3CL1 is considered to be independent from sCX3CL1.
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