Absence of C–C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model

Liou, Jiin-Tarng; Yuan, Hui-Bih; Mao, Chih-Chieh; Lai, Ying-Shu; Day, Yuan-Ji

doi:10.1016/j.pain.2012.03.008

Cited by 54 publications

(42 citation statements)

References 63 publications

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“…Likewise, CCL3 −/− mice have reduced pelvic pain [34]. CCL5 −/− mice also have reduced pain [35], and CCL5 injection into the brain results in enhanced pain [36]. Similarly, intrathecal injection of CCL7 enhanced pain, whereas administration of anti-CCL7 antibodies reduced pain.…”

Section: Discussionmentioning

confidence: 99%

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

et al. 2014

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Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1−/− animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1−/− mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.

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Section: Discussionmentioning

confidence: 99%

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

et al. 2014

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“…Blocking CCL2 (monocyte chemoattractant protein-1 (MCP-1) ) signaling via a neutralizing antibody prevented the development of SNL-induced sensory hypersensitivities (Gao et al, 2009). Further, mice either lacking CCL5 (regulated on activation, normal T cell expressed and secreted (RANTES)) or peritoneally administered with a selective CCL5 receptor antagonist, Met-RANTES, showed reduced hypersensitivity following partial sciatic nerve ligation (Liou et al, 2013; Liou et al, 2012). Injections of CCL5 either peripherally (Oh et al, 2001) or centrally (Benamar et al, 2008) induced hypersensitivities in rat.…”

Section: Introductionmentioning

confidence: 99%

Calcitonin gene-related peptide contributes to peripheral nerve injury-induced mechanical hypersensitivity through CCL5 and p38 pathways

Malon

Cao

2016

Journal of Neuroimmunology

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The role of calcitonin gene related peptide (CGRP) in neuropathic pain was investigated in a mouse model of neuropathic pain, spinal nerve L5 transection (L5Tx). Intrathecal injection (i.t) of CGRP8–37, a CGRP antagonist, significantly reduced L5Tx-induced mechanical hypersensitivity and lumbar spinal cord CCL5 expression. i.t. injection of a CCL5 neutralizing antibody significantly inhibited L5Tx-induced mechanical hypersensitivity. Further, pre-treatment with a p38-inhibitor, SB203580, was able to reduce CGRP-induced mechanical hypersensitivity, but not CGRP-induced CCL5 production. Our data indicate that CGRP can play its pro-nociceptive role through both a spinal cord CCL5-dependent, p38-independent pathway, and a p38-depenented, CCL5-independent pathway.

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“…CCL3 and CCL5 were considered as the more probable candidates to play such a role due to their well-recognized hypernociceptive effects [6,9,29] and to the previous description that both CCL3 [7,11,30] and CCL5 [10,19,31] can be up-regulated under different pathological conditions. In contrast, we have not considered the possible involvement of CCL7 (monocyte chemotactic protein 3, MCP-3) because, although it can also bind to CCR1, its pro-nociceptive effects seem related to CCR2 activation [32].…”

Section: Discussionmentioning

confidence: 99%

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

Llorián-Salvador

González-Rodríguez

Lastra

et al. 2016

Basic Clin Pharma Tox

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Chemokines are chemotactic cytokines whose involvement in nociceptive processing is being increasingly recognized. Based on the previous description of the involvement of CC chemokine receptor type 1 (CCR1) in pathological pain, we have assessed the participation of CCR1 and its endogenous ligands CCL3 and CCL5 in hyperalgesia and allodynia in mice after acute inflammation with carrageenan and chronic inflammation with complete Freund's adjuvant (CFA). The subcutaneous administration of the CCR1 antagonist J113863 (3-30 mg/kg; 30 min. before) dose dependently inhibited carrageenan-and CFA-evoked thermal hyperalgesia and mechanical allodynia produced by CFA, but not by carrageenan. The maximal dose of J113863 did not modify the increase in paw thickness induced by carrageenan or CFA. An almost ten times augmentation of CCL3 levels was detected by ELISA assays in both carrageenan and CFA paws, but not in spinal cords of inflamed mice, whereas CCL5 concentrations remained unaltered. Accordingly, a marked increase of CCL3 mRNA expression was observed in inflamed paws, with CCL3 protein detected in neutrophils and macrophages by immunohistochemical experiments. The intraplantar administration of an anti-CCL3 antibody (0.3-3 lg) blocked thermal hyperalgesia in carrageenan-and CFA-inflamed mice as well as CFA-evoked mechanical allodynia. Our data suggest that the increased concentrations of CCL3 present in inflamed tissues can be involved in acute and chronic inflammatory hyperalgesia as well as in chronic mechanical allodynia, and that these hypernociceptive symptoms can be counteracted by its neutralization with an antibody or by the blockade of CCR1 receptors.Chemokines are chemotactic cytokines involved in inflammatory processes, mainly by favouring immune cell recruitment. Several chemokines activate nociceptive pathways at both peripheral and central level, and this explains their participation in different types of pathological pain [1][2][3][4]. CC chemokine receptor type 1 (CCR1) is expressed in neurons of dorsal root ganglia (DRG) [5,6] as well as in central structures related to pain [7,8]. The stimulation of CCR1 expressed in nociceptors causes Ca 2+ influx and enhances capsaicin responsiveness [6], and the local administration of CCR1 agonists elicits nociceptive behaviours in mice [9,10]. CCR1 is up-regulated in sensory neurons [11] and the spinal cord [7,12] after nerve injury and increased CCR1 mRNA has also been measured in rats 24 hr after receiving carrageenan [13], supporting its involvement in nociceptive processing. Functionally, it has been reported that some types of neuropathic pain can be alleviated by blocking CCR1 expression with siRNA [11], and that the administration of a CCR1 antagonist can prevent some types of murine bone cancer pain [10] and partially reduce writhing responses in mice receiving intraperitoneal acetic acid or mechanical hyperalgesia in inflamed mice [14]. Among the different chemokines able to activate CCR1 [15], CCL3 (MIP-1a, macrophage inflammatory protein-1...

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Absence of C–C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model

Cited by 54 publications

References 63 publications

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

Calcitonin gene-related peptide contributes to peripheral nerve injury-induced mechanical hypersensitivity through CCL5 and p38 pathways

Involvement of CC Chemokine Receptor 1 and CCL3 in Acute and Chronic Inflammatory Pain in Mice

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