Abstract
The chemokine C-C-chemokine ligand 2 (CCL2) (formerly known as MCP, macrophage chemotactic
protein) is one of the important genes upregulated in different types of pain both
in animals and humans. CCL2 governs the recruitment of C-C chemokine receptor 2-expressing
monocytes into inflamed tissue. In contrast to neutrophilic chemokines, intraplantar
injection of CCL2 in Wistar rats recruited macrophages and neutrophils and simultaneously
lowered nociceptive thresholds. CCL2-induced hyperalgesia was abolished by prior systemic
leukocyte depletion by cyclophosphamide and was reconstituted by local adoptive transfer
of donor macrophages but not of neutrophils. Antagonists against transient receptor
potential vannilloid 1 inhibited thermal and against transient receptor potential
ankyrin 1 blocked mechanical hyperalgesia. Peripheral but not central activation of
cyclooxygenase-2 (Cox-2) were critical for CCL2-induced hyperalgesia. In vitro CCL2
did not directly stimulate Cox-2 expression or prostaglandin E2 formation but slightly
enhanced the formation of reactive oxygen species in monocytes and macrophages. In vivo,
increased immunoreactivity for 4-hydroxy-2-nonenal (4-HNE), a downstream product of
reactive oxygen species and known inducer of Cox-2, was observed and colocalized with
Cox-2 in ED1 (CD68) positive infiltrating cells. No hyperalgesia, 4-HNE, or Cox-2
immunoreactivity was seen in leukocyte-depleted rats that were reconstituted with
macrophages in the absence of CCL2, supporting the important role of CCL2.
Perspective
CCL2 plays a dual role: 1) promoting monocyte/macrophage recruitment into tissue;
and 2) potentially stimulating macrophages in the tissue to produce 4-HNE and subsequently
Cox-2, all resulting in the induction of hyperalgesia via transient receptor potential
vannilloid 1 and transient receptor potential ankyrin 1. This encourages pharmacological
efforts targeting CCL2/C-C chemokine receptor 2 and macrophages for treatment of inflammatory
pain.
Key words
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Article info
Publication history
Published online: May 20, 2013
Accepted:
February 26,
2013
Received in revised form:
February 17,
2013
Received:
September 25,
2012
Footnotes
Supported by a grant from the Interdisciplinary Center of Clinical Studies, University of Wuerzburg, Germany (N-112).
The authors declare that they have no competing interests.
Identification
Copyright
© 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.
