CCR2-Mediated Uptake of Constitutively Produced CCL2: A Mechanism for Regulating Chemokine Levels in the Blood.

Autor: Zhao BN; ChemoCentryx, Inc., Mountain View, CA 94043; and., Campbell JJ; ChemoCentryx, Inc., Mountain View, CA 94043; and jcampbell@ChemoCentryx.com., Salanga CL; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093., Ertl LS; ChemoCentryx, Inc., Mountain View, CA 94043; and., Wang Y; ChemoCentryx, Inc., Mountain View, CA 94043; and., Yau S; ChemoCentryx, Inc., Mountain View, CA 94043; and., Dang T; ChemoCentryx, Inc., Mountain View, CA 94043; and., Zeng Y; ChemoCentryx, Inc., Mountain View, CA 94043; and., McMahon JP; ChemoCentryx, Inc., Mountain View, CA 94043; and., Krasinski A; ChemoCentryx, Inc., Mountain View, CA 94043; and., Zhang P; ChemoCentryx, Inc., Mountain View, CA 94043; and., Kufareva I; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093., Handel TM; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093., Charo IF; ChemoCentryx, Inc., Mountain View, CA 94043; and., Singh R; ChemoCentryx, Inc., Mountain View, CA 94043; and., Schall TJ; ChemoCentryx, Inc., Mountain View, CA 94043; and.
Jazyk: angličtina
Zdroj: Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Dec 15; Vol. 203 (12), pp. 3157-3165. Date of Electronic Publication: 2019 Nov 01.
DOI: 10.4049/jimmunol.1900961
Abstrakt: C-C chemokine receptor 2 (CCR2) is a key driver of monocyte/macrophage trafficking to sites of inflammation and has long been considered a target for intervention in autoimmune disease. However, systemic administration of CCR2 antagonists is associated with marked increases in CCL2, a CCR2 ligand, in the blood. This heretofore unexplained phenomenon complicates interpretation of in vivo responses to CCR2 antagonism. We report that CCL2 elevation after pharmacological CCR2 blockade is due to interruption in a balance between CCL2 secretion by a variety of cells and its uptake by constitutive internalization and recycling of CCR2. We observed this phenomenon in response to structurally diverse CCR2 antagonists in wild-type mice, and also found substantially higher CCL2 plasma levels in mice lacking the CCR2 gene. Our findings suggest that CCL2 is cleared from blood in a CCR2-dependent but G protein (Gα i , Gα s or Gα q/11 )-independent manner. This constitutive internalization is rapid: on a given monocyte, the entire cell surface CCR2 population is turned over in <30 minutes. We also found that constitutive receptor internalization/recycling and ligand uptake are not universal across monocyte-expressed chemokine receptors. For example, CXCR4 does not internalize constitutively. In summary, we describe a mechanism that explains the numerous preclinical and clinical reports of increased CCL2 plasma levels following in vivo administration of CCR2 antagonists. These findings suggest that constitutive CCL2 secretion by monocytes and other cell types is counteracted by constant uptake and internalization by CCR2-expressing cells. The effectiveness of CCR2 antagonists in disease settings may be dependent upon this critical equilibrium.
(Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze: MEDLINE
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