The cytokine midkine supports neutrophil trafficking during acute inflammation by promoting adhesion via β2 integrins (CD11/CD18)

• Published in: Blood 2014-03, Vol.123 (12), p.1887-1896
• Main Authors: Weckbach, Ludwig T., Gola, Anita, Winkelmann, Michael, Jakob, Sascha M., Groesser, Leopold, Borgolte, Julia, Pogoda, Frank, Pick, Robert, Pruenster, Monika, Müller-Höcker, Josef, Deindl, Elisabeth, Sperandio, Markus, Walzog, Barbara
• Format: Article
• Language: English
• Subjects: Animals; CD11 Antigens - physiology; CD18 Antigens - genetics; CD18 Antigens - physiology; Cell Adhesion - immunology; Cell Adhesion - physiology; Cytokines - immunology; Cytokines - physiology; Humans; Inflammation - immunology; Inflammation - pathology; Inflammation - physiopathology; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Intercellular Signaling Peptides and Proteins - physiology; Low Density Lipoprotein Receptor-Related Protein-1 - immunology; Low Density Lipoprotein Receptor-Related Protein-1 - physiology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Midkine; Nerve Growth Factors - genetics; Nerve Growth Factors - immunology; Nerve Growth Factors - physiology; Neutrophils - immunology; Neutrophils - pathology; Neutrophils - physiology; Receptors, LDL - immunology; Receptors, LDL - physiology; Tumor Suppressor Proteins - immunology; Tumor Suppressor Proteins - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-06-510875

Emerging evidence suggests a role of the cytokine midkine (MK) in inflammation. In this study, its functional relevance for recruitment of polymorphonuclear neutrophils (PMNs) during acute inflammation was investigated. Intravital microscopy and histologic analysis of tumor necrosis factor-α-stimulated cremaster muscle venules revealed severely compromised leukocyte adhesion and extravasation in MK−/− mice compared with MK+/+ animals. Systemic administration of recombinant MK completely rescued the adhesion defect in MK−/− mice. In a hind limb ischemia model, leukocyte accumulation in MK−/− mice was significantly diminished compared with MK+/+ animals. However, MK did not lead to an inflammatory activation of PMNs or endothelial cells suggesting that it does not serve as classical proinflammatory cytokine. Unexpectedly, immobilized MK mediated PMN adhesion under static and flow conditions, whereas PMN-derived MK was dispensable for the induction of adhesion. Furthermore, adhesion strengthening remained unaffected by MK. Flow cytometry revealed that immobilized, but not soluble MK, significantly promoted the high affinity conformation of β2 integrins of PMNs. Blocking studies of low-density lipoprotein receptor-related protein 1 (LRP1) suggested that LRP1 may act as a receptor for MK on PMNs. Thus, MK seems to support PMN adhesion by promoting the high affinity conformation of β2 integrins, thereby facilitating PMN trafficking during acute inflammation. •MK promotes PMN recruitment during the acute inflammatory response.•MK and β2 integrins (CD11/CD18) cooperate in mediating PMN adhesion during acute inflammation.