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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 (?M?2, 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 ?MI domain, the major ligand-binding region of Mac-1, and PTN. Using peptide libraries, we found that in PTN the ?MI domain bound sequences enriched in basic and hydrophobic residues, indicating that PTN conforms to the general principle of ligand-recognition specificity of the ?MI 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.

SUBMITTER: Shen D

PROVIDER: S-EPMC5704470 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Shen Di D Podolnikova Nataly P NP Yakubenko Valentin P VP Ardell Christopher L CL Balabiyev Arnat A Ugarova Tatiana P TP Wang Xu X

The Journal of biological chemistry 20170922 46

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 recept ...[more]

PMID: 28939773

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Project description:Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1β (pIL-6 = 0.031, pIL-1β = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes. KEY MESSAGES: Little is known about leukocyte cytokine responses in patients with mitochondrial diseases. Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses. Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression. Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.

Dataset Information

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

Publications

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

Similar Datasets

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