Pleiotrophin, a multifunctional cytokine and growth factor, induces leukocyte responses through the integrin Mac-1

Abstract

Pleiotrophin (PTN) is a multifunctional, cationic, glycosaminoglycan-binding cytokine and growth factor involved in numerous physiological and pathological processes, including tissue repair and inflammation-related diseases. PTN has been shown to promote leukocyte responses by inducing their migration and expression of inflammatory cytokines. However, the mechanisms through which PTN mediates these responses remain unclear. Here, we identified the integrin Mac-1 (αMβ2, CD11b/CD18) as the receptor mediating macrophage adhesion and migration to PTN. We also found that expression of Mac-1 on the surface of human embryonic kidney (HEK) 293 cells induced their adhesion and migration to PTN. Accordingly, PTN promoted Mac-1-dependent cell spreading and initiated intracellular signaling manifested in phosphorylation of Erk1/2. While binding to PTN, Mac-1 on Mac-1-expressing HEK293 cells appears to cooperate with cell-surface proteoglycans because both anti-Mac-1 function-blocking mAb and heparin were required to block adhesion. Moreover, biolayer interferometry and NMR indicated a direct interaction between the αI domain, the major ligand-binding region of Mac-1, and PTN. Using peptide libraries, we found that in PTN the αI domain bound sequences enriched in basic and hydrophobic residues, indicating that PTN conforms to the general principle of ligand-recognition specificity of the αI domain toward cationic proteins/peptides. Finally, using recombinant PTN-derived fragments, we show that PTN contains two distinct Mac-1-binding sites in each of its constitutive domains. Collectively, these results identify PTN as a ligand for the integrin Mac-1 on the surface of leukocytes and suggest that this interaction may play a role in inflammatory responses.

Leukocyte integrin Mac-1 (CD11b/CD18, αMβ2, CR3) acts as a functional receptor for platelet factor 4

“…3C). Similar effects of heparin and anti-Mac-1 function blocking reagents on adhesion of Mac-1-HEK293 cells as well as monocytes have been documented for other Mac-1 ligands (18,19,27), including a multifunctional cationic glycosaminoglycan-binding cytokine and growth factor pleiotrophin (28). These data suggest that on the surface of cells that express HS glycosmanoglycans, HSPGs may serve as co-receptors with Mac-1 to mediate PF4 binding.…”

“…PF4 has a high affinity for heparin (24) and negatively charged proteoglycans (25,26). Furthermore, it is well-known that Mac-1 on monocytes and Mac-1-HEK293 cells cooperates with cell-surface heparan sulfate proteoglycans (HSPGs) during cell adhesion to the extracellular matrix protein CCN1 and to several other Mac-1 ligands (18,19,27,28). To investigate whether HSPGs participate in cell adhesion to PF4, we examined the effect of heparin on adhesion of Mac-1-HEK293 cells.…”

Oxygen-glucose deprivation and reoxygenation on human cerebral organoids alters expression related to lipid metabolism

“…In the brain, YWHAE is involved in directing the movement of nerve cells by binding to other proteins (Toyo-oka et al, 2003). Pleiotrophin (PTN) plays important roles in cell growth and survival, cell migration, and the expression of inflammatory cytokines (Shen et al, 2017). YWHAE and PTN are mainly expressed in the cerebral cortex (Kido et al, 2014; Shen et al, 2017).…”

“…Pleiotrophin (PTN) plays important roles in cell growth and survival, cell migration, and the expression of inflammatory cytokines (Shen et al, 2017). YWHAE and PTN are mainly expressed in the cerebral cortex (Kido et al, 2014; Shen et al, 2017). POSTN leads to decreased apoptosis during hypoxia (Aukkarasongsup et al, 2013).…”

Interaction between the integrin Mac-1 and signal regulatory protein α (SIRPα) mediates fusion in heterologous cells

“…Partial inhibition of adhesion by mAb M1/70 suggested that in addition to Mac-1, other structures on the surface of macrophages may be involved in binding to mSIRP␣. To investigate this possibility, we examined whether heparan sulfate and chondroitin sulfate proteoglycans, which commonly cooperate with Mac-1 in adhesion to its ligands (22)(23)(24)(25), are involved in adhesion to SIRP␣. Whereas preincubation of RAW264.7 cells with 10 g/ml of each heparin, chondroitin sulfate A, and chondroitin sulfate B partially inhibited adhesion (35 Ϯ 1, 47 Ϯ 8, and 28 Ϯ 3%, respectively), their combination with mAb M1/70 did not potentiate the inhibitory effect of the mAb (Fig.…”