The cytokine midkine supports neutrophil trafficking during acute inflammation by promoting adhesion via β2 integrins (CD11/CD18).
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.
Walter-Brendel-Centre of Experimental Medicine, Department of Cardiovascular Physiology and Pathophysiology, and.
Ludwig T
LT
Weckbach
Anita
A
Gola
Michael
M
Winkelmann
Sascha M
SM
Jakob
Leopold
L
Groesser
Julia
J
Borgolte
Frank
F
Pogoda
Robert
R
Pick
Monika
M
Pruenster
Josef
J
Müller-Höcker
Elisabeth
E
Deindl
Markus
M
Sperandio
Barbara
B
Walzog
D000818:Animals; D018845:CD11 Antigens / Q000502:physiology; D018821:CD18 Antigens / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology / Q000502:physiology; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000276:immunology / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D011973:Receptors, LDL / Q000276:immunology / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000276:immunology / Q000502:physiology
D018845:CD11 Antigens; D018821:CD18 Antigens; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; C066254:MDK protein, human; C582105:Mdk protein, mouse; D009414:Nerve Growth Factors; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000078792:Midkine