Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease

Abstract

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis

“…CX3CL1 is the only member of the CX3C class of chemokines, and it has well-documented roles in ECs. CX3CL1 is a unique chemokine that combines the properties of a chemoattractant and an adhesion molecule [42][43][44][45].…”

“…The resulting FKN-CX3CR1 axis transduces several well-characterized signaling pathways that lead to the activation of several transcription factors (e.g., signal transducer and activator of transcription protein [STAT], nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κβ], and cAMP/Ca2+ response element binding protein [CREB]) and the inhibition of other factors (e.g., members of the class O forkhead box transcription factor [FOXO]) [44,102,157]. Most of these CX3CR1 signaling pathways are shared with other chemokine receptors, including:…”

“…Once activated, Gαi can go on to interact with downstream effectors [156]. The effect on gene transcription is achieved by activating the signal transducer and activator of transcription protein (STAT), nuclear factor kappalight-chain-enhancer of activated B cells (NF-κβ) and cAMP/Ca2+ response element binding protein (CREB), while inhibiting the members of the class O of forkhead box transcription factors (FOXO) [44,102,157]. The involvement of the phospholipase C (PLC)/ protein kinase C (PKC) pathway in intracellular divalent calcium cations (Ca2+) mobilization that may influence chemotaxis is well documented [158,159].…”

“…As a unique chemokine expressed in many cell types that exhibits chemoattractant (sFKN) and pro-angiogenic effects and the typical features of an adhesion molecule (mFKN), FKN has been intensively studied in the context of carcinogenesis and metastasis [220,246,300]. The presence of a signaling pathway associated with only the metabotropic receptor CX3CR1 facilitates the interpretation of the observed relationships and narrows potential therapeutic targets [44,194,207].…”

Microvascular Obstruction in Acute Myocardial Infarction, a Potential Therapeutic Target

“…Imaging biomarkers have also linked inflammation to plaque instability and the development of acute MI [ 21 , 22 , 23 ]. Whether inflammation plays a role in exacerbating MVO is yet to be determined [ 24 ].…”