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. 2024 Feb 29;109(7):2060–2072. doi: 10.3324/haematol.2023.284921

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Copyright© 2024 Ferrata Storti Foundation

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Figure 3. — Molecular properties of CXCL8 and its cognate receptors CXCR1 and CXCR2. CXCL8 interacts with its cognate receptors CXCR1 and CXCR2, which are predominantly expressed on neutrophils but may also appear on lymphoid immune cells or other myeloid cells such as megakaryocytes. In contrast with CXCR1, the CXCR2 receptor appears over-expressed in CD34⁺ cells from patients with myelofibrosis compared to healthy controls. CXCR1 and CXCR2 are G protein-coupled receptors and CXCL8 mainly tends to bind CXCR2 as a dimer, while CXCR1 strongly binds CXCL8 as a monomer. After activation of the GPCR, the G-protein dissociates into Gα and G|3/y subunits. The separated Gβ/y subunits activate phospholipase C (32 (PLC(32) which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) and then forms the secondary messenger molecules diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3 stimulates the release of Ca2⁺ from the endoplasmic reticulum. Release of Ca2⁺ activates kinases, such as protein kinase C (PKC), which play a role in cellular migration or degranulation. Besides PLC|32, the G(3/y subunit may also activate phosphoinositide 3-kinase y (PI3Ky) which phosphorylates PIP2 into phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 may activate kinases such as AKT (protein kinase B) and hereby stimulate cellular proliferation. Activation of phospholipase D (PLD) is mediated by CXCR1 activation and plays a role in the release of reactive oxygen-nitrogen species (ROS/RNS) and neutrophil extracellular traps (NET). The activity of CXCL8 may be reduced by heterodimerization with CXCL4 (also known as plate-let factor-4 [PF-4]) or interaction with the Duffy antigen/receptor for chemokines (DARC) which functions as a scavenger receptor. CXCL8 properties may be influenced by post-translational changes, such as truncation by proteases, amino-acid side-chain modifications (e.g., citrullination or tyrosine nitration) or variations in quaternary structure (i.e., formation of monomers/dimers). AKT: protein kinase B; CXCL4: chemokine (CXC motif) ligand 4 (also known as platelet factor-4); CXCL8: CXC chemokine ligand 8 (also known as interleukin-8 [IL-8]), DAG: diacylglycerol; DARC: Duffy antigen/receptor for chemokines; IP3: inositol 1,4,5-triphosphate; PI3Ky: phosphoinositide 3-kinase y; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; KC: protein kinase C; PLD: phospholipase D.