Osteopontin Undergoes Polymerization in Vivo and Gains Chemotactic Activity for Neutrophils Mediated by Integrin α9β1
| Autor: | Dean Sheppard, Norihisa Nishimichi, Chun Chen, Hiromi Hayashita-Kinoh, Haruo Matsuda, Yasuyuki Yokosaki |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Integrins
Neutrophils medicine.medical_treatment Integrin Glycobiology and Extracellular Matrices Biochemistry Mice Thrombin stomatognathic system GTP-Binding Proteins In vivo Cell Line Tumor medicine Animals Humans Protein Glutamine gamma Glutamyltransferase 2 Osteopontin Molecular Biology Transglutaminases biology Chemistry Chemotaxis technology industry and agriculture Wild type Cell Biology Molecular biology In vitro Cytokine Neutrophil Infiltration biology.protein Female Protein Multimerization medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 286:11170-11178 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.189258 |
| Popis: | Osteopontin (OPN) is an integrin-binding inflammatory cytokine that undergoes polymerization catalyzed by transglutaminase 2. We have previously reported that polymeric OPN (polyOPN), but not unpolymerized OPN (OPN*), attracts neutrophils in vitro by presenting an acquired binding site for integrin α9β1. Among many in vitro substrates for transglutaminase 2, only a few have evidence for in vivo polymerization and concomitant function. Although polyOPN has been identified in bone and aorta, the in vivo functional significance of polyOPN is unknown. To determine whether OPN polymerization contributes to neutrophil recruitment in vivo, we injected OPN* into the peritoneal space of mice. Polymeric OPN was detected by immunoblotting in the peritoneal wash of mice injected with OPN*, and both intraperitoneal and plasma OPN* levels were higher in mice injected with a polymerization-incompetent mutant, confirming that OPN* polymerizes in vivo. OPN* injection induced neutrophil accumulation, which was significantly less following injection of a mutant OPN that was incapable of polymerization. The importance of in vivo polymerization was further confirmed with cystamine, a transglutaminase inhibitor, which blocked the polymerization and attenuated OPN*-mediated neutrophil recruitment. The thrombin-cleaved N-terminal fragment of OPN, another ligand for α9β1, was not responsible for neutrophil accumulation because a thrombin cleavage-incompetent mutant recruited similar numbers of neutrophils as wild type OPN*. Neutrophil accumulation in response to both wild type and thrombin cleavage-incompetent OPN* was reduced in mice lacking the integrin α9 subunit in leukocytes, indicating that α9β1 is required for polymerization-induced recruitment. We have illustrated a physiological role of molecular polymerization by demonstrating acquired chemotactic properties for OPN. |
| Databáze: | OpenAIRE |
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