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Published online before print July 28, 2008

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(Journal of Leukocyte Biology. 2008;84:1101-1108.)
© 2008 by Society for Leukocyte Biology

An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo

Tracy M. Handel^*, Zoë Johnson^,1, David H. Rodrigues, Adriana C. dos Santos, Rocco Cirillo, Valeria Muzio, Simona Riva, Matthias Mack^||, Maud Déruaz, Frédéric Borlat, Pierre-Alain Vitte, Timothy N. C. Wells, Mauro M. Teixeira and Amanda E. I. Proudfoot^,2

Merck Serono Geneva Research Centre, Geneva, Switzerland;
^* Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA;
Departmento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;
Instituto di Ricerche Biomediche "A. Marxer," Colleretto Giacosa, Italy; and
^|| Department of Internal Medicine II, University of Regensburg, Regensburg, Germany

² Correspondence: Merck Serono Geneva Research Centre, 9, Chemin des Mines, CH-1211, Geneva, Switzerland. E-mail: amanda.proudfoot{at}merckserono.net

We demonstrated recently that P8A-CCL2, a monomeric variant of the chemokine CCL2/MCP-1, is unable to induce cellular recruitment in vivo, despite full activity in vitro. Here, we show that this variant is able to inhibit CCL2 and thioglycollate-mediated recruitment of leukocytes into the peritoneal cavity and recruitment of cells into lungs of OVA-sensitized mice. This anti-inflammatory activity translated into a reduction of clinical score in the more complex inflammatory model of murine experimental autoimmune encephalomyelitis. Several hypotheses for the mechanism of action of P8A-CCL2 were tested. Plasma exposure following s.c. injection is similar for P8A-CCL2 and wild-type (WT) CCL2, ruling out the hypothesis that P8A-CCL2 disrupts the chemokine gradient through systemic exposure. P8A-CCL2 and WT induce CCR2 internalization in vitro and in vivo; CCR2 then recycles to the cell surface, but the cells remain refractory to chemotaxis in vitro for several hours. Although the response to P8A-CCL2 is similar to WT, this finding is novel and suggests that despite the presence of the receptor on the cell surface, coupling to the signaling machinery is retarded. In contrast to CCL2, P8A-CCL2 does not oligomerize on glycosaminoglycans (GAGs). However, it retains the ability to bind GAGs and displaces endogenous JE (murine MCP-1) from endothelial surfaces. Intravital microscopy studies indicate that P8A-CCL2 prevents leukocyte adhesion, while CCL2 has no effect, and this phenomenon may be related to the mechanism. These results suggest that oligomerization-deficient chemokines can exhibit anti-inflammatory properties in vivo and may represent new therapeutic modalities.

Key Words: inflammation • antagonist • obligate monomer • EAE