ReviewCXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization
Introduction
As a physiological component, pain acts as an alarm to withdraw from an injurious condition to reduce tissue damage. However, in pathological pain conditions, such as chronic pain, this unpleasant experience may start after tissue damage that remains subsequent to tissue healing, even in the absence of stimulation potentially dangerous. In such circumstance, pain becomes harmful and is detrimental to pursuance of an acceptable quality of life by an individual. Chronic pain is commonly triggered by nerve injury and chronic peripheral inflammation. These insults induce the release of neurotransmitters, lipid mediators, fragments of the complement system, neurotrophic factors, cytokines and chemokines in both the central (CNS) and peripheral nervous system (PNS). Together, these and other components mediate the “leukocyte-neuron–glia multi-directional communication” which leads to peripheral and central sensory neurons sensitization. These interactions generally result in genesis and maintenance of pathological pain. Therefore, nerve injury or peripheral inflammation induces activation and proliferation of glial cells, leukocyte recruitment and increases neuronal excitability in the PNS and CNS, and both are involved in the nociceptive transmission changes (Eijkelkamp et al., 2012, Ma and Quirion, 2006). The elucidation of how these cells and mediators interact with each other can provide better targets for drug development of more effective and selective analgesics. Among all these mediators, chemokines are emerging as attractive targets. They act peripherally and centrally in modulating nociceptive transmission and seem to be important to switch from physiological to pathological pain conditions (Cunha et al., 2005, Gao and Ji, 2010, Ji et al., 2014, Souza et al., 2013, Zarpelon et al., 2016).
Chemokines are small chemotactic cytokines which can control the trafficking and migratory behavior of peripheral immune and/or glial cells (Bajetto et al., 2001, Cross and Woodroofe, 1999, Tanabe et al., 1997). However, their participation in induction and maintenance of pathological pain states, such as inflammatory and neuropathic pain, is not restricted to their chemotactic activities. Glial and neuronal cells can also be activated by chemokines, which contributes to peripheral sensitization and neuroplasticity, whereby they modulate the pain process. Some chemokines have a prominent role in pain modulation, such as CX3CL1, CCL2, CXCL1, CXCL8, CCL7 and CCL21 (Biber and Boddeke, 2014, Imai et al., 2013, Ji et al., 2014, Ke et al., 2016, Ren and Dubner, 2010, Souza et al., 2013, Wang et al., 2009). In accordance, new drugs targeting chemokine receptors have been developed to treat diseases, including inflammatory and neuropathic pain, which are undergoing evaluation in pre-clinical (Cunha et al., 2008a, Lopes et al., 2016) or clinical trials (Horuk, 2009). CXCL1 is one of the chemokines with significant role in pain modulation, which can be produced both peripherally and centrally. The described effects of CXCL1 to mediate inflammatory and neuropathic pain development occur through activation of its principal cognate receptor, C-X-C chemokine receptor type 2 (CXCR2), which is expressed by PNS and CNS neurons. Herein, we review and discuss what is known about the role of CXCL1/CXCR2 signaling pathways in the pathophysiology of pain focusing on its mechanisms in peripheral and central nervous system.
Section snippets
CXCL1: background
CXCL1 is a C-X-C chemokine family member containing a Glu-Leu-Arg (ELR) motif at its amino terminus. It is one of the major chemoattractants for neutrophils (De Filippo et al., 2008, Frink et al., 2007, Watanabe et al., 1989). CXCL1 is also known as keratinocytes-derived chemokine (KC) in mice, cytokine-induced neutrophil chemoattractant type-1 (CINC-1) in rats, and as growth-regulated oncogene alpha (GROα) in humans where acts similarly to interleukin-8 (IL-8; CXCL8) (Verri et al., 2006,
CXCR1 and CXCR2 signaling pathways triggered by CXCL1
When activated, seven transmembrane receptors (7TMRs) are able to trigger parallel signaling pathways with different efficacies, mostly involving heterotrimeric G proteins or multifunctional adapter proteins. This phenomenon has been referred as “biased agonism” (Shukla et al., 2011). Nonetheless, CXCL1 promotes cellular responses through activation of 7TMRs CXCR1 and CXCR2. It is a partial CXCR1 agonist for inhibition of cAMP signaling (through Gα inhibitory, Gαi), a full agonist to β-arrestin
Physiological role of CXCL1/CXCR2 in nervous system
The most extensively studied CXCL1 receptor, CXCR2, is expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord (Horuk et al., 1997, Popivanova et al., 2003). Additionally, in the CNS, CXCR2 is also constitutively expressed by oligodendrocyte
Peripheral expression of CXCL1/CXCR2 and its effects in nociceptive transmission
The production of CXCL1 at the inflammatory site was well described by our and other groups during the last decades (Carreira et al., 2013, Cunha et al., 2003, Cunha et al., 2005, Koch et al., 1995, Lorenzetti et al., 2002, Shibata et al., 1996). During peripheral tissue inflammation, the local production of CXCL1 is mediated by local cells, including resident macrophages. Within the peripheral inflammatory site, CXCL1 contributes to the hyperalgesia (increased sensitivity to pain) by
Concluding remarks
Chronic pain is induced and maintained by mediators released by leukocytes, neurons and glial cells which trigger neuronal sensitization peripherally and centrally. Current therapies for chronic pain are limited to only reducing symptoms, usually by reducing neural activity (Scholz and Woolf, 2007). However, less than 50% of the patients who use one of these drugs achieve satisfactory pain relief. In several cases, combination therapy is necessary, which causes a greater number of side effects
Acknowledgments
This review received funding from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, grant 451/2008), and 2013/08216-2 (Center for Research in Inflammatory Diseases). The authors are grateful to Prof. Peter Reinach for polishing the manuscript; Marcela Davoli, Mingchuan Lim and Carlo Campa for their suggestions.
References (116)
Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration
Brain Behav. Immun.
(2017)Chemokine signaling via the CXCR2 receptor reinforces senescence
Cell
(2008)- et al.
Fine tuning the transcriptional regulation of the CXCL1 chemokine
Prog. Nucleic Acid Res. Mol. Biol.
(2003) - et al.
The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines
J. Neuroimmunol.
(2010) Chemokines and their receptors in the central nervous system
Front. Neuroendocrinol.
(2001)CGRP receptors in the control of pain and inflammation
Curr. Opin. Pharmacol.
(2009)The role of fractalkine (CX3CL1) in regulation of CD4(+) cell migration to the central nervous system in patients with relapsing-remitting multiple sclerosis
Clin. Immunol.
(2015)Chemokine CXCL1 enhances inflammatory pain and increases NMDA receptor activity and COX-2 expression in spinal cord neurons via activation of CXCR2
Exp. Neurol.
(2014)Chemokine receptor CXCR2 in dorsal root ganglion contributes to the maintenance of inflammatory pain
Brain Res. Bull.
(2016)Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues
Blood
(2008)
Chemokine CXCL8 modulates GluR1 phosphorylation
J. Neuroimmunol.
Molecular cloning of gene sequences regulated by platelet-derived growth factor
Cell
Maturation and release of interleukin-1beta by lipopolysaccharide-primed mouse Schwann cells require the stimulation of P2X7 receptors
J. Biol. Chem.
Wallerian degeneration and peripheral nerve conditions for both axonal regeneration and neuropathic pain induction
Ann. Anat.
Chemokines, neuronal-glial interactions, and central processing of neuropathic pain
Pharmacol. Ther.
Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury
Cell Rep.
Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat
Neuroscience
A comparison of post-receptor signal transduction events in Jurkat cells transfected with either IL-8R1 or IL-8R2. Chemokine mediated activation of p42/p44 MAP-kinase (ERK-2)
FEBS Lett.
Chemokine receptor CXCR2 regulates the functional properties of AMPA-type glutamate receptor GluR1 in HEK cells
J. Neuroimmunol.
Diverging signal transduction pathways activated by interleukin-8 and related chemokines in human neutrophils: interleukin-8, but not NAP-2 or GRO alpha, stimulates phospholipase D activity
Blood
Expression of AMPA-type glutamate receptors in HEK cells and cerebellar granule neurons impairs CXCL2-mediated chemotaxis
J. Neuroimmunol.
DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain
Pharmacol. Res.
The role of keratinocyte-derived chemokine (KC) on hyperalgesia caused by peripheral nerve injury in mice
Neuropharmacology
Immune and inflammatory mechanisms in neuropathic pain
Brain Res. Rev.
Beta-arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation
Blood
Expression of the chemokine receptors CXCR1 and CXCR2 in rat oligodendroglial cells
Brain Res. Dev. Brain Res.
Treatment of neuropathic pain: an overview of recent guidelines
Am. J. Med.
The platelet-derived growth factor-inducible KC gene encodes a secretory protein related to platelet alpha-granule proteins
J. Biol. Chem.
Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptor CXCR2 in monkey hippocampus after ischemia-reperfusion
Brain Res.
Biased agonism as a mechanism for differential signaling by chemokine receptors
J. Biol. Chem.
On the mechanism and significance of ligand-induced internalization of human neutrophil chemokine receptors CXCR1 and CXCR2
J. Biol. Chem.
Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity
Neuroscience
Differential changes in the concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-2 in exudate during rat lipopolysaccharide-induced inflammation
Cytokine
Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling
Trends Biochem. Sci.
Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain
Neuron
Hyperalgesia in experimental neuropathy is dependent on the TNF receptor 1
Exp. Neurol.
Hyperalgesia due to nerve injury: role of prostaglandins
Neuroscience
The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration
Cell
Differential regulation of the CXCR2 chemokine network in rat brain trauma: implications for neuroimmune interactions and neuronal survival
Neurobiol. Dis.
Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development?
Pharmacol. Ther.
Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain
Front. Cell. Neurosci.
Neutrophils recruited by CXCR1/2 signalling mediate post-incisional pain
Eur. J. Pain
Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice
Brain
Chemokines induce migration and changes in actin polymerization in adult rat brain microglia and a human fetal microglial cell line in vitro
J. Neurosci. Res.
The critical role of leukotriene B4 in antigen-induced mechanical hyperalgesia in immunised rats
Br. J. Pharmacol.
A cascade of cytokines mediates mechanical inflammatory hypernociception in mice
Proc. Natl. Acad. Sci. U. S. A.
Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice
Br. J. Pharmacol.
Crucial role of neutrophils in the development of mechanical inflammatory hypernociception
J. Leukoc. Biol.
Neutrophil chemokines KC and macrophage-inflammatory protein-2 are newly synthesized by tissue macrophages using distinct TLR signaling pathways
J. Immunol.
Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC
Neurosci. Bull.
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