Page 52 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis
press lipopolysaccharide-induced CXC chemokine (LIX) or GCP-2, which is the murine homolog of human CXCL5 and CXCL6, as most potent neutrophil-attracting chemokine. As LIX/GCP-2 is able to bind both CXCR1 and CXCR2, it is also considered to be a functional homolog of human CXCL8.48 While the functional characteristics of murine CXCR2 have been well characterized, those of murine CXCR1 remain largely unknown. Consequently, most of our knowledge is derived from studies focusing on CXCR2. Interestingly, human CXCL8 is able to bind both murine CXCR1 and CXCR2.63
G. Vermeersch et al. CXCL8 in primary myelofibrosis
CXCL8 concentrations are increased independently from mutational status within PB plasma of patients with PMF.64,65 Similarly, within BM CXCL8, concentrations are increased amongst all MPN subtypes (PV, ET, and PMF) and no significant association between cytokine levels and mutational status is observed.31 Within MPN, increased concentration of CXCL8 correlates with adverse outcomes, including reduced OS. Nonetheless, the exact role of CXCL8 and its cognate recep- tors in myelofibrosis are still unknown. Single-cell cytokine
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 main- ly 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 Gb/γ subunits. The separated Gb/γ subunits activate phospholipase C b2 (PLCb2) which hydrolyzes phos- phatidylinositol 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 PLCb2, the Gb/γ subunit may also activate phosphoinositide 3-kinase γ (PI3Kγ) 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 neu- trophil 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 recep- tor. 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-tri- phosphate; PI3Kγ: phosphoinositide 3-kinase γ; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol (3,4,5)-tri- sphosphate; KC: protein kinase C; PLD: phospholipase D.
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