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 Blood, 1 August 2008, Vol. 112, No. 3, pp. 493-503.
Prepublished online as a Blood First Edition Paper on May 14, 2008; DOI 10.1182/blood-2007-08-108316.

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Submitted August 22, 2007
Accepted April 22, 2008

Regulation of D6 chemokine scavenging activity by ligand and Rab11-dependent surface upregulation

Raffaella Bonecchi*, Elena M Borroni, Achille Anselmo, Andrea Doni, Benedetta Savino, Massimiliano Mirolo, Monica Fabbri, Venkatakrishna R Jala, Bodduluri Haribabu, Alberto Mantovani, and Massimo Locati

Immunology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
Instituto di Patologia Generale, University of Milan, Milan, Italy
Unit of Leukocyte Biology, DIBIT-Scientific Institute San Raffaele, Milan, Italy
James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY, United States

* Corresponding author; email: raffaella.bonecchi{at}humanitas.it.

The decoy receptor D6 plays a non-redundant role in the control of inflammatory processes through scavenging of inflammatory chemokines. However it remains unclear how it is regulated. Here we show that D6 scavenging activity relies on unique trafficking properties. Under resting conditions, D6 constitutively recycled through both a rapid wortmannin (WM)-sensitive and a slower brefeldin A (BFA)-sensitive pathway maintaining low levels of surface expression that required both Rab4 and Rab11 activities. In contrast to "conventional" chemokine receptors that are downregulated by cognate ligands, chemokine engagement induced a dose-dependent BFA-sensitive Rab11-dependent D6 redistribution to the cell membrane and a corresponding increase in chemokine degradation rate. Thus, the energy-expensive constitutive D6 cycling through Rab11 vesicles allows a rapid, ligand concentration-dependent, increase of chemokine scavenging activity by means of receptor redistribution to the plasma membrane. D6 is not regulated at a transcriptional level in a variety of cellular contexts, thus ligand-dependent optimization of its scavenger performance represents a rapid and unique mechanism allowing D6 to control inflammation.


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