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Originally published online as doi:10.1189/jlb.0405224 on October 4, 2005

Published online before print October 4, 2005
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(Journal of Leukocyte Biology. 2005;78:1210-1214.)
© 2005 by Society for Leukocyte Biology

Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems

Ning Zhang*,{dagger} and Joost J. Oppenheim*,1

* Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Maryland; and
{dagger} Department of Chemical Biology and State Key Laboratory of Molecular Dynamic and Stable Structures, College of Chemistry, Peking University, Beijing, China

1 Correspondence: Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Building 560, Room 21-89A, Frederick, MD 21702-1201. E-mail: Oppenhei{at}ncifcrf.gov

ABSTRACT

Chemokine receptors, a family of Gi protein-coupled receptors responsible for cell migration, are widely expressed by cells of immune and nervous systems. Activation of receptors on the surface of leukocytes, such as opioid, vasoactive intestinal peptide, or adenosine receptors, often has inhibitory effects on chemokine receptors by a mechanism termed heterologous desensitization, resulting in suppression of immune responses. Conversely, activation of chemokine receptors also induces heterologous desensitization of µ-opioid receptors (MOR), a class of key analgesic receptors on neurons. Furthermore, prior exposure of neuronal cells to chemokine treatment enhances the sensitivity of transient receptor potential vanilloid 1 (TRPV1), a heat- and ligand-gated calcium channel, which is critical for sensing of pain. Consequently, during inflammation, activation of chemokine receptors on neurons contributes to hyperalgesia by inhibiting MOR and concomitantly sensitizing TRPV1 via Gi protein-mediated signaling pathways. These observations suggest that the crosstalk between chemokine receptors and neuropeptide membrane receptors serves as a bridge between the immune and nervous systems.

Key Words: hyperalgesia • opioid • TRPV1

CHEMOKINE RECEPTOR EXPRESSION BY NEURONS

Chemokines are a group of 7- to 14-kd polypeptides, which were initially discovered at sites of inflammation [1 , 2 ]. They play a vital role in regulating leukocyte migration by activating members of a family of seven transmembrane receptors [3 ]. These receptors sense a shallow gradient of the chemokines along the cell body and direct the cells to move to sites of higher ligand concentration through coupling to heterotrimeric Gi proteins. Recent studies have revealed that chemokine receptors are also critical in brain development, angiogenesis, and wound healing [1 , 4 ]. Chemokine receptors, originally identified on the surface of leukocytes, have been detected in the central nervous system (CNS). In addition to the macrophage-like microglial cells of the CNS, chemokine receptors are also expressed on astrocytes, oligodendrocytes, and neurons [4 ]. These chemokine receptors participate in inflammatory and neurodegenerative conditions of CNS, as well as in brain development and synaptic activities [5 , 6 ]. The expression of chemokine receptors can also be readily assessed on peripheral sensory neurons and CNS neurons. For example, immunohistochemical co-staining with isolectin B4 and substance P indicates the presence of these receptors on afferent nociceptive neurons of the dorsal root ganglia (DRG). Furthermore, when isolated and grown in cell cultures, the primary neurons from DRG respond to stimulation by a spectrum of chemokines with a transient Ca2+ influx, indicating that these receptors are functional [7 ]. Therefore, cells of the immune and nervous system express functional chemokine receptors.

HETEROLOGOUS DESENSITIZATION OF CHEMOKINE RECEPTORS

The activity of a chemokine receptor is often down-regulated by other G protein-coupled receptors (GPCR) in the same cell by the process of heterologous desensitization, which is a mechanism by which one type of receptor down-regulates another GPCR activity [8 ]. Activation of one type of GPCR can result in phosphorylation of C-terminal cytosolic tails of other GPCR by second messenger-mediated kinases, such as protein kinase A (PKA) or PKC. Phosphorylated receptors lose their capacity to couple to the downstream heterotrimeric G protein and therefore, become insensitive to stimulation. Pretreatment of leukocytes with opioids, a family of neuronal hormones, impairs chemokine receptor function, which may contribute to the immunosuppressive effects of opioids [9 , 10 ]. This is based on opioid interaction with µ, {kappa}, or {delta} opioid GPCR induced heterologous desensitization of chemokine receptors [9 , 11 ]. Opioids elicit modest signal transduction responses in leukocytes, as indicated by low chemotactic potency, but are incapable of inducing transient Ca2+ influx [12 ]. The inhibitory crosstalk between opioids and chemokine receptors is also limited and involves only Ca2+-independent PKC. It has been noted that opioid treatment also enhances the level of circulating corticosterone and epinephrine, which may contribute to opioid-induced immunosuppression.

Another neuropeptide, vasoactive intestinal peptide (VIP), exerts profound immunosuppressive effects by desensitizing chemokine receptors [13 , 14 ]. VIP treatment induces phosphorylation of certain chemokine receptors, resulting in a decrease in chemokine-induced G protein activation. VIP infusion in a murine delayed-type hypersensitivity model inhibits the recruitment of monocytes and lymphocytes. Thus, increasing evidence suggests that neuronal peptides, such as opioids and VIP, are capable of down-regulating leukocyte function by down-regulating chemokine receptors.

MECHANISM OF HETEROLOGOUS DESENSITIZATION OF OPIOID RECEPTORS BY CHEMOKINE RECEPTORS

Chemokine receptors can also regulate the function of neurons. Recent studies reveal that proinflammatory chemokines enhance the sensing of pain [7 , 15 ], which is a host defense avoidance mechanism. In the presence of tissue damage and/or inflammation, the sensing of pain alarms the host to respond at central and peripheral levels to avoid or to contain dangers. Although pain is a general symptom for many diseases, such as cancer, neuropathy, and rheumatoid arthritis, it has often been under-recognized and under-treated. Currently, there are primarily three types of anti-pain medicine available: opioids, cyclooxygenase 1/2 inhibitors, and local anesthetics. To develop highly specific and potent anti-pain therapy, it is necessary to investigate the molecular mechanism of the causes of pain. Inflammation is a major cause of pain, especially chronic pain. Galen first has recognized that pain, along with loss of function, swelling, redness, and heat, is one of the key characteristics of inflammation. We will review our recent evidence showing that inflammatory chemokines promote pain, based on the crosstalk among chemokine receptors, analgesic opioid receptors, and pain-sensing transient receptor potential vanilloid 1 (TRPV1).

Opiates have long been used as an analgesic herbal medicine. In 1973, opioid receptors were identified on neuronal cells. DNA sequence analysis reveals that opioid receptors belong to a superfamily of seven transmembrane receptors and consist of three subtypes: µ-, {delta}-, and {kappa}-opioid receptors [16 , 17 ]. These receptors exert their biological function by coupling to heterotrimeric Gi proteins [18 ]. This results in a spectrum of downstream effects, including activation of G protein-coupled inward rectify potassium channels (GIRK), inhibition of various plasma membrane calcium channels, and cyclic adenosine monophosphate production [19 20 21 ]. Two mechanisms have been proposed for opioid receptors to counter the sensing of pain. Activation of GIRK inhibits the depolarization of the neuronal membrane, preventing the excitation of sensory neurons and the transmission of the signals along the spinal cord to the CNS. Inhibition of calcium channels of plasma membranes will impair the release of neurotransmitters, which is important for the propagation of pain signals. Opioid receptor-mediated signaling transduction is regulated tightly at different levels in a manner similar to many other GPCR. At the receptor level, prolonged exposure to ligands results in adaptation of these receptors through a process called homologous desensitization [22 ]. During the process of homologous desensitization, activated GPCR recruits G protein receptor kinases (GRK) in a G protein-independent manor. GRK phosphorylates cytoplasmic tails of GPCR and interrupts the coupling between GPCR and G proteins, resulting in desensitization effects. Sometimes, phosphorylation of GPCR also causes a decrease in the cell surface receptor level through arrestin-mediated receptor internalization, imposing further inhibitory effects on GPCR activity. Furthermore, activation of other GPCR also often dampens the function of opioid receptors via heterologous desensitization, which typically involves the PKA/PKC family [8 ].

The first clue, implicating chemokine-induced heterologous desensitization of opioid receptor function, comes from the study of leukocyte chemotaxis [11 ]. Activation of CC chemokine receptor 1 (CCR1), CCR2, CCR5, CCR7, and CXC chemokine receptor 4 results in the impairment of µ-opioid receptor (MOR)-mediated chemotaxis of leukocytes. Recently, the inhibitory effects of chemokines on MOR function were also detected in CCR1:MOR/human embryonic kidney cells and DRG neurons [23 ]. It has been well documented that chemokines induce dissociation of Gi proteins, which in turn activates phospholipase C ß II (PLCßII) to hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3; Fig. 1 ), which initiates a transient release of Ca2+ from endoplasmic reticulum by activating IP3 receptors. DAG and Ca2+ are potent activators of PKC, a family of 12 Ser/Thr kinases. Pertussis toxin and PKC inhibitors block chemokine-induced down-regulation of MOR function, indicative of a role of Gi and PKC in this heterologous desensitization. Ca2+-dependent and -independent PKC is involved in the phosphorylation of MOR and down-regulates its coupling efficiency to the G protein.



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  		Figure 1. Crosstalk among chemokine, opioid, and TRPV1 receptors. In sensory neurons, treatment with proinflammatory chemokines, CC chemokine ligand 3 (CCL3), down-regulates opioid receptor function through PKC, resulting in hyperalgesia. Phosphorylation of the cytoplasmic tail and intracellular loops of opioid receptors by PKC decouples the receptor from downstream Gi proteins, resulting in a decrease in receptor function. CCL3 also enhances the sensitivity of TRPV1, a "pain" receptor, through a signal transduction cascade involving Gi protein, PLCß, and PKC. PLCß hydrolyzes phosphoinositol 4,5-biphosphate (PIP2), an endogenous inhibitor of TRPV1, thereby sensitizing the TRPV1 pain receptor (IP3).

 
The in vitro observation of desensitization of MOR on primary neurons was confirmed by a cold-water tail flick assay [11 ]. When a rat’s tail is immersed in cold water, a sensation of pain is generated, and the rat responds with a flick of its tail. The latency of the tail-flick response reciprocally correlates with the sensitivity of the rat to pain. Introduction of a specific ligand for MOR, Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO), into the rat periaqueductal gray center (PAG) significantly enhances the tail-flick latency, indicative of MOR-mediated analgesic effects. Preadministration of chemokines impairs this DAMGO-induced analgesic effect (e.g., restores the rapid tail-flick response), suggesting that a chemokine induced heterologous desensitization of the opioid receptor in the PAG restores the sensing of pain.

CHEMOKINE RECEPTOR SIGNALS SENSITIZE TRPV1 PAIN RECEPTORS

In addition to inhibiting analgesic opioid receptors, chemokines enhance the sensitivity of a pain-sensing, heat- and ligand-gated calcium channel TRPV1 [7 ]. Pain is detected by a group of afferent sensory neurons, nociceptors. Recently, the first pain receptor TRPV1 (also called vanilloid receptor 1) was identified as a six transmembrane calcium channel and is highly expressed on nociceptors [24 , 25 ]. Noxious stimuli, such as capsaicin, heat, and acid, induce the opening of this calcium channel. Consequently, the membrane is depolarized, and the action potential is propagated to the CNS as a pain signal. During inflammation, a variety of cellular mediators, such as bradykinin, nerve growth factor, and prostaglandin E2, has been shown to contribute to hyperalgesia by regulating the expression, sensitivity, and adaptation of TRPV1. Four molecular mechanisms have been revealed to enhance the perception of pain through TRPV1 by these cellular mediators: enhanced production of endogenous ligands for TRPV1; enhanced sensitivity of TRPV1 due to PKC phosphorylation; inhibition of adaptation due to PKA phosphorylation; and removal of endogenous inhibitor PI(4,5)P2 by PLC [26 27 28 29 30 ].

Increasing evidence from several mouse behavioral assays suggests that proinflammatory chemokines, such as CCL2 and -3 and keratinocyte-derived chemokine, enhance the sensing of pain by TRPV1 [7 , 15 , 31 ]. Three possible mechanisms have been proposed to explain this sensitization effect. First, it is likely that chemokine receptors sensitize TRPV1 on sensory neurons and contribute to an increase in pain perception based on the following facts [7 ]. The expression pattern of CCR1, a representative, proinflammatory chemokine receptor, partially overlaps with that of TRPV1 on the sensory neurons of DRG, and ~39 ± 3% of DRG neurons express both receptors. Pretreatment with CCL3 (macrophage-inflammatory protein-1{alpha}), an endogenous ligand for CCR1, enhanced the sensitivity of TRPV1 to capsaicin by three- to fivefold, as measured by calcium flux responses in vitro. The sensitization effects are likely a result of the removal of PI(4,5)P2, a TRPV1 endogenous inhibitor, and phosphorylation of this calcium channel by PKC (Fig. 1) . Intraplantar injection of CCL3 into the footpad of a mouse enhances the rate of mouse hind-paw withdrawal from the painful stimulation by heat, indicating the relevance of the in vitro observation. The fact that a proinflammatory chemokine, by interacting with its receptor on small diameter neurons, indirectly sensitizes TRPV1 suggests that the process of receptor cross-sensitization may contribute to hyperalgesia during inflammation. The second possibility is that the transient calcium flux induced by proinflammatory chemokines is sufficient to induce a depolarization of the sensory neurons and to generate a signal to be perceived as pain in the CNS [15 ]. However, it is unlikely that every neuronal calcium influx will result in the perception of pain, since opioids, which also induce neuronal calcium influx, are not painful. Finally, it is also likely that a network of cytokines and chemokines generated by local inflammation may induce the production of prostaglandin, bradykinin, and other cellular mediators, which can also sensitize TRPV1 indirectly [31 ]. Further investigation is required to determine which mechanism plays a major role in chemokine-induced sensitization of TRPV1.

Crosstalk among TRPV1, opioid, and chemokine receptors provides a novel mechanism to explain inflammation-induced hyperalgesia. Chemokines desensitize analgesic opioid receptors and sensitize TRPV1 pain receptors. The opioid and TRPV1 pathways warn the host of the existence of a pathological painful condition. Blocking chemokine receptor-induced activation of PKC and PLC may reduce the painful symptom significantly. Furthermore, a decrease in nociceptive neuron activity will in turn reduce the secretion of proinflammatory neurotransmitters, such as CGRP and substance P. Therefore, blocking effects of proinflammatory chemokines may serve as an effective approach to block the positive feedback loops between inflammation and hyperalgesia.

ANTI-INFLAMMATORY EFFECTS OF DESENSITIZING CHEMOKINE RECEPTORS

Bidirectional crosstalk between chemokine and neuronal receptors provides a mechanism for integrating neuronal and immune responses (Fig. 2 ). The concept that receptor crosstalk may play a major role in modulating neuroimmune communication was evaluated further by studies of the effects of adenosine on immune and neuronal systems. It is known that children with adenosine deaminase deficiency are severely immunodeficient based on the failure to degrade adenosine [32 ]. Furthermore, the immunosuppressive effects of methotrexate therapy on autoimmune disease states are based in part on the accumulation of adenosine [33 ]. We have found that adenosine, via its A2a receptors, also desensitizes the in vitro chemotactic response of leukocytes to chemokines [34 , 35 ]. Furthermore, in vivo administration of adenosine inhibits the recruitment of leukocytes by chemokines to an inflammatory site (our unpublished data). It is interesting that adenosine also seems to play an important role in regulating the sensing of pain. Disruption of A2a adenosine receptors renders mice insensitive in hot plate and tail-flick assays [36 ]. Therefore, studies about the A2a adenosine receptor further support the notion that receptor crosstalk may serve as a general mechanism to integrate the immune and nervous system.



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  		Figure 2. Inflammation induces hyperalgesia. Inflammation is associated with an increase in proinflammatory chemokines and extracellular adenosine. Chemokines desensitize analgesic opioid receptors and sensitize TRPV1 pain receptors on DRG neurons, contributing to hyperalgesia. Conversely, opioids induce heterologous desensitization of chemokine receptors on leukocytes, resulting in immunosuppressive effects. Activation of adenosine A2a receptors down-regulates inflammation through desensitizing chemokine receptors and inhibiting the production of proinflammatory cytokines. Disruption of A2a receptors results in hypoalgesic effects on mice, indicative of a role of adenosine in the sensation of pain. CXCL8, CXC chemokine ligand 8.

 
CONCLUSION

These studies have revealed a complex communication network between receptors of the immune and nervous system. Chemokine receptors play a critical role through their interaction with TRPV1, adenosine, opioid, VIP, and as yet unidentified receptors. The data show that the process of heterologous desensitization has physiologically relevant in vivo consequences. Furthermore, sensitization can also be demonstrated. Prostaglandin, histamine, chemokines, and other proinflammatory agents can prime and enhance the response of heat- and ligand-gated calcium channels. Consequently, one can envision a potentially broad array of interactions between various types of receptors provided. Crosstalk between receptors within one cell results in a multiplicity of biological consequences.

ACKNOWLEDGEMENTS

This research was entirely supported by the intramural research program of the NCI, NIH.

Received April 24, 2005; revised August 24, 2005; accepted August 29, 2005.

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