Biochimica et Biophysica Acta 1851 (2015) 61–65
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Review
Lysophosphatidic acid and signaling in sensory neurons☆ Ronald P.J. Oude Elferink ⁎, Ruth Bolier, Ulrich H. Beuers Tytgat Institute for Liver and Intestinal Research, Academic Medical Center Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands
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Article history: Received 30 May 2014 Received in revised form 22 August 2014 Accepted 5 September 2014 Available online 16 September 2014 Keywords: Lysophosphatidic acid Autotaxin Cholestasis Pruritus Neuropathic pain
a b s t r a c t Lysophosphatidic acid is a potent signaling lipid molecule that has initially been characterized as a growth factor. However, later studies have revealed many more functions such as modulation of cell shape, cell migration, prevention of apoptosis, platelet aggregation, wound healing, osteoclast differentiation, vasopressor activity, embryo implantation, angiogenesis, lung fibrosis, hair growth and more. The molecule mainly acts through the activation of a set of at least 6 G-protein-coupled receptors (LPA1–6), but intracellular LPA was also shown to signal through the activation of the nuclear receptor PPARγ. In this short review we discuss the recent observations which suggest that in pathological conditions LPA also modulates signaling in sensory neurons. Thus, LPA has been shown to play a role in the initiation of neuropathic pain and, more recently, a relation was observed between increased LPA levels in the circulation and cholestatic itch. The mechanism by which this occurs remains to be elucidated. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. © 2014 Elsevier B.V. All rights reserved.
1. LPA synthesis Lysophosphatidic acid is a phospholipid metabolite that can be generated by different intra- and extracellular pathways. The intracellular pathway can start by the generation of phosphatidic acid from phospholipid by phospholipase D. It can also be generated by the acylation of glycerophosphate by glycerophosphate acyltransferase or by the phosphorylation of diacylglycerol by diacylglycerol kinase (DGK). The subsequent action of PLA1 or PLA2 then generates LPA with the fatty acyl chain on the sn2 or sn1 position, respectively. The fact that LPA often bears an unsaturated acyl chain shows that PLA1 should be involved because the sn2 position does not generally have a saturated acyl chain whereas the sn1 position does. The family of PLA1 enzymes has not been very extensively studied, however. One PLA1 deserves particular interest as it seems to have a specific role in LPA signaling in hair follicle stimulation. Two genes have been identified to play a causative role in hair growth deficiency. One is the lipase H (LIPH) gene that when mutated gives rise to hypotrichosis and wooly hair [21]. Lipase H is a phospholipase A1 expressed in hair follicles. This enzyme is localized in the plasma membrane and has preference for phosphatidic acid (within the membrane) as a substrate. In addition, mutations in the gene encoding the LPA6 (P2Y5) receptor give rise to the same phenotype [41,46]. Hence, it is very likely that these two proteins function in the same pathway of regulation of hair growth.
☆ This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. ⁎ Corresponding author. Tel.: +31 20 5663828; fax: +31 20 5669190. E-mail address: [email protected] (R.P.J. Oude Elferink).
http://dx.doi.org/10.1016/j.bbalip.2014.09.004 1388-1981/© 2014 Elsevier B.V. All rights reserved.
Most of the signaling functions of LPA occur through binding to LPAspecific G-protein coupled receptors and thereby involve extracellular levels of LPA. However, there are also intracellular functions. LPA has been characterized as an activating ligand of the nuclear receptor PPARγ [33,47], which is particularly involved in the regulation of energy metabolism and adipogenesis. In addition, it has recently been shown that intracellular LPA is able to directly stimulate the transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a nonselective cation channel that functions as an integrator of signals in sensory neurons (see below). Other channels have also been reported as targets of intracellular LPA [10]. The production of blood-borne LPA starts with the action of secretory PLA1 or PLA2 or by lecithin-cholesterol acyltransferase. All these reactions produce lysophospholipid which can subsequently be converted to LPA by the enzyme autotaxin. Autotaxin is a phospholipase D in blood that is secreted by various cell types such as the adipose tissue, choroid plexus, kidney, and lung intestine [15]. Although ATX was originally thought to be a membrane-associated enzyme, it has become clear that it is secreted into blood where it converts lysophospholipid into LPA. However, the enzyme binds to target cells via integrin and heparan sulfate proteoglycans. Binding to heparin sulfate is mediated by the exon 12-encoded polybasic insert that is only present in the alternatively spliced isoform ATX-α. In contrast, all ATX isoforms bind to β1 and β3 integrins via the second of two somatomedin B binding (SMB) motifs in the N-terminal part of all isoforms of the protein. This integrin-mediated binding is thought to play an important role in the delivery of LPA to LPA receptors on target cells. Crystallography of the protein has revealed a tunnel in the protein which has been suggested to function as an LPA exit channel allowing the delivery of LPA to its cognate receptors [36,39].
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2. LPA receptors At present 6 receptors have been recognized to be responsive to LPA. The classical receptors (LPA1, LPA2 and LPA3) were earlier designated as Edg (endothelial differentiation gene) receptors. All six receptors are G-protein coupled receptors, but their intracellular signaling pathways differ. Thus, LPA1, LPA2 and LPA4 relay to Gα12/13, Gαq/11 and Gαi/o isoforms, whereas LPA3 relays to Gαq/11 and Gαi/o and LPA5 relays to Gα12/13 and Gαq/11. LPA6 relays to Gα12/13 and Gαi/o. Importantly, LPA4 and LPA6 also relay to Gαs, which through its induction rather than the reduction of cAMP may give rise to opposite effects. In this way, and depending on cell-specific expression of the different LPA receptors, a quite diverse scala of signaling functions may be achieved. As an example, LPA4 was found to have opposite effects compared to LPA1-3 in terms of cell motility [26] and osteoblast differentiation [29]. There are differences in the specificities of the receptors for various forms of LPA [4]. All LPA receptors have the highest reactivity with LPA containing oleic (18:1), linoleic (18:2), or linolenic (18:3) followed by palmitoleoyl (16:1) and arachidonoyl (20:4) LPA. In contrast to LPA1 and LPA3, LPA2 is also well activated by myristoyl (14:0) and palmitoyl (16:0) LPA. Interestingly, LPA6 appears to have a preference for LPA with the fatty acyl chain on the sn2 position in contrast to the other receptors that are more or less equally activated by LPA molecules with the fatty acyl chain in the sn1 or sn2 position [52]. This fits with the fact that LPA6 (P2Y5) is thought to be activated by LPA generated by Lipase H, which is a phospholipase A1 [41,46]. LPA1-6 receptors are expressed at varying levels in the CNS during development and postnatal life [12]. In neurons LPA1 and LPA2 are expressed with the latter more abundantly [40]. LPA5 is also expressed in sensory and motor neurons in the spinal cord and appears to have a functional role in pain processing. Astrocytes express LPA1-5 whereas oligodendrocytes express LPA1 and LPA2 [12]. Also in peripheral sensory neurons the expression of LPA receptors has been reported, although the identification of subsets of LPA-responsive sensory neurons (such as in different fiber types as well as pain vs. itch) is incomplete yet. 3. The role of LPA in neuropathic pain Neuropathic pain is defined as ‘Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ [30]. It is a form of chronic pain that is not caused though stimulation of sensory neurons by “physiological” pain stimuli but rather by dysfunction or injury of the fibers. This dysfunction is a consequence of underlying diseases such as (among others) diabetes, cancer and multiple sclerosis. Injury may have taken place at different levels: central (such as in spinal cord injury or brain infarction) or peripheral (due to systemic diseases or ischemic neuropathy). Multiple and diverse mechanisms have been identified for the development of neuropathic pain, including peripheral sensitization, structural reorganization, demyelination and central sensitization. Together these events lead to alteration in the production of neuropeptides and their cognate receptors and function of ion channels. Among many processes that have been described to play a role in neuropathic pain, an extensive body of work also points to a role for LPA signaling. It was shown in 2004 by the group of Ueda that the initiation of neuropathic pain requires LPA signaling [19]. For research purposes, a frequently used animal model for neuropathic pain is partial sciatic nerve injury which causes prominent allodynia (pain perception upon an otherwise unpainful stimulus) and hyperalgesia that last for at least two weeks. In mice, allodynia and hyperalgesia are monitored by the paw pressure test and the tail flick test. Applying this model to mice, Inoue et al. [19] found that pain perception was strongly reduced in LPA1 knockout mice but not in LPA2 knockout mice. Conversely, intrathecal injection of LPA caused hyperalgesia and allodynia that lasted for about 7 days. In wild type mice LPA injection was accompanied by demyelination of dorsal root fibers, a phenomenon that is observed with neuropathic pain. In LPA1−/− mice this demyelination was
reduced. Demyelination reduces the isolation of the fibers so that action potentials generated in one axon can lead to membrane potential changes in adjacent axons that put them closer to threshold, perhaps even causing an ectopic action potential. It was hypothesized that LPA at high concentrations is generated at the site of the wound by activated platelets, degenerating axons and/or damaged neurons and that LPA1 receptors, also present on Schwann cells, mediate demyelination. Similar results were reported by Ahn et al. [1] using the model of LPA injection in the trigeminal ganglia of rats. Subsequently, Inoue et al. [17] showed that partial sciatic nerve injury caused reduced hyperalgesia in Atx+/− mice, suggesting that ATX is involved in the generation of LPA during nerve injury. This experiment cannot be performed in a full Atx knockout as these animals are not viable [50]. Inoue et al. also observed that overstimulation of pain fibers by the treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, caused production of LPA. LPA was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA in the presence of recombinant autotaxin. These observations suggested that the overstimulation of fibers leads to increased production of LPC the substrate from which ATX produces LPA, but this was not directly measured [18]. More recently, data were provided which demonstrated that LPA release causes a feed-forward LPA production in the early phase of neuropathic pain by the activation of the LPA3 receptor [31]. It was speculated that nerve injury may induce the production of LPA at the early phase and subsequently cause LPA1 receptor activation to induce neuropathic pain. The mechanism of demyelination upon LPA release was further investigated and seems to involve calpaindependent downregulation of myelin-associated protein (MAG) [51] in dorsal roots. Recently, the group of Chun implicated yet another LPA receptor, LPA5, in the mechanism of initiation of neuropathic pain [27]. LPA5 mRNA was detected in a subset of DRG neurons. LPA5 was also expressed in the dorsal horn area of the lumbar spinal cord, and as expected, signal transduction was absent in these tissues in LPA5deficient mice. Interestingly, normal pain sensation was not altered in LPA5-deficient mice, whereas the development of nerve injuryinduced neuropathic pain (partial sciatic nerve ligation) was abolished. This protection was accompanied by the downregulation of phosphorylated cAMP response element binding protein (pCREB) signaling in spinal cord dorsal horn neurons. In contrast to what was observed in LPA1−/− mice, the LPA5 loss did not prevent demyelination indicating that LPA5 signals through another pathway. While this study did not find a difference in normal pain perception in LPA5−/− mice, Callaerts-Vegh et al. [9] did report reduced nociception in Freund's adjuvant-induced inflammatory pain in these animals.
4. The role of LPA in (cholestatic) itch Itch is defined as the sensation that urges to scratch and is induced by a host of endogenous and exogenous compounds. It can have a great variety of causes from skin diseases to cancer and systemic diseases but it can also be psychogenic. Until about 15 years ago it was thought that itch is mediated through the same fibers as pain, but that itch sensation is caused by subliminal activation of pain neurons. However, the present paradigm is that itch is mediated by separate fibers from (inflammatory) pain although the two are transduced by very similar small diameter C-fibers with unmyelinated nerve endings [2,6]. Thus, the activation of both itch and pain neurons requires the function of the non-specific cation channel TRPV1. The theory of separate itch fibers is supported by the observation of specific neurotransmitters for itch (gastrin-releasing peptide [48] and natriuretic peptide B [35]). Conversely, there is a clear interaction between itch and pain, because at the spinal level pain signals suppress itch signaling through interneurons. The transcription factor Bhlhb5 is transiently expressed in the dorsal
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horn of the developing spinal cord to regulate a unique population of inhibitory interneurons that inhibit itch [43]. Pruritus is a frequent symptom in many hepatobiliary disorders, particularly those with cholestatic features [8,28]. This form of itching is designated cholestatic pruritus as bile secretion and/or flow is impaired in these disorders. Cholestatic pruritus may be caused by impaired hepatocellular secretory function as seen in intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), toxin- or druginduced cholestasis, and chronic viral hepatitis B and C infections. It may also occur upon intrahepatic bile duct damage and secondary hepatocyte secretory failure as in primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and pediatric cholestatic syndromes such as the Alagille syndrome. Finally, cholestasis due to the obstruction of the intrahepatic or extrahepatic bile duct draining system is observed in cholestasis caused by gallstones, PSC, cholangiocellular carcinoma, obstructive tumors of the pancreatic head or enlarged lymph nodes located in the hilar region, bile duct adenomas, or biliary atresia. Interestingly, the prevalence of pruritus varies considerably between these disorders. Pruritus is the defining symptom of women suffering from ICP [14] and is experienced by a large proportion of patients with PBC and PSC. In contrast, pruritus is less frequently reported by patients with obstructive cholestasis [34] and chronic hepatitis C infections [11], and rarely associated with chronic hepatitis B patients, non-alcoholic fatty liver disease, and alcoholic or nonalcoholic steatohepatitis even when cholestasis is present [23]. In various cholestatic disorders such as PBC and ICP it is an early symptom that can even be experienced before the diagnosis of cholestasis. Although chronic pruritus is a very distressing symptom, the cause of cholestatic itch has been unclear for a long time and still is poorly understood. The general working hypothesis is that compounds that accumulate in blood during cholestasis are normally efficiently secreted into bile. Besides useful compounds like bile salts, also many toxins and endogenous waste products are secreted into bile either or not after being metabolized and/or conjugated with various groups like glucuronic acid sulfate and glutathione. Many of these compounds are reabsorbed in the intestine after deconjugation and in this way undergo enterohepatic circulation. Originally, it was hypothesized that during cholestasis bile salts accumulate in the circulation cause itch. Indeed it has been observed that bile salts are capable to induce in vitro mast cell degranulation [42]. However, this occurs at bile salt concentrations that are well above those at which cholestatic itch is observed. Furthermore, a relation between serum bile salt levels and the extent of itch has never been established [5,13]. Interestingly, the group of Corvera [3] recently postulated that the G protein-coupled receptor TGR5, which is activated by bile salts and neurosteroids, may play a role in the generation of cholestatic itch. They showed that TGR5 is expressed on neurons in the dorsal root ganglia of mice and this expression partially overlaps with TRPV1 and GRP, suggesting that TGR5 is expressed on itchselective sensory neurons. In vivo experiments in TGR5 overexpressing mice revealed an increased basal scratch activity and intradermal injection of deoxycholate (DCA) evoked scratch behavior in wild type mice, that was partly reduced in TGR5−/− mice and increased in TGR5-overexpressing mice. These findings would support a primary role for TGR5 in itch induction. Unfortunately, for most of the in vitro experiments relatively high concentrations of unconjugated DCA (up to 100 μM) were used. Again, these concentrations are much higher than those observed in pathological conditions, like PBC and ICP, associated with itch. A second hypothesis has been that during cholestasis endogenous opioids are increased which would decrease pain perception and thereby increase itch [20]. It was indeed found that cholestasis in rats leads to increased serum levels of enkephalins as well as increased mRNA levels of preproenkephalin in the liver [7,49]. However, although increased
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levels of serum μ-opioid can be observed in some cholestatic patients there is no relation between these levels and the extent of itch [24]. More recently, Kremer et al. [24] have performed a screen for compounds in cholestatic serum that activate neuronal cells with the aim to identify a new “itch factor”. This screen revealed increased levels of LPA in sera from women with intrahepatic cholestasis of pregnancy (ICP) as well as patients with primary biliary cirrhosis (PBC) that had itch. The increased levels of LPA correlated with highly significant increases in serum autotaxin (ATX) levels and the latter even correlated with the severity of itch. In a later report it was demonstrated that effective therapy for cholestatic itch, such as biliary diversion and rifampicin treatment, led to significant decrease of serum ATX [25]. It was also shown that ATX expression in HepG2 cells could be downregulated by treatment with rifampicin and that this involved the activation of the nuclear receptor PXR [25]. Finally, it has been reported that intradermal injection of LPA in mice leads to significant and dose-dependent scratch behavior [16,22,44]. Shimizu et al. [44] showed, in addition, that this scratch behavior could be inhibited by the administration of the LPA1 and LPA3 receptor antagonists Ki16425. Hashimoto et al. [16] demonstrated that the administration of ketotifen, a mast cell stabilizer, also diminished LPA-induced scratch behavior, suggesting that it occurs through mast cell degranulation. These data suggest that there may be a causative role for ATX-mediated LPA production in the activation of itch neurons. It remains to be further investigated whether this occurs primarily through mast cell activation or also through direct activation of LPA receptors on itch neurons. This is particularly important as cholestatic itch is refractory to antihistamines [23]. It is of note that LPA is also capable of directly activating the nonselective cation channel TRPV1 that is involved in generation of action potentials in sensory neurons [38]. It was demonstrated in patch clamp studies, that LPA stimulates TRPV1 channel opening but does so considerably faster and stronger in inside-out membrane patches (i.e. intracellular signaling) than in right side out patches (i.e. extracellular signaling). LPA seems to interact with a proposed intracellular PIP2 binding site on TRPV1 in which the lysine 710 residue participates. Thus, this report suggests a role for intracellular rather than extracellular LPA. Since LPA is a relatively hydrophilic lipid molecule, that will not passively cross the plasma membrane of cells, it remains to be shown how relevant this type of activation is with regard to extracellularly generated LPA. 5. Autotaxin and other conditions of chronic itch Kremer et al. [25] demonstrated that serum autotaxin levels not only are elevated in cholestasis but also are significantly increased, albeit to a much lesser extent, in serum from patients with atopic dermatitis and in patients with Hodgkin's disease. The latter aspect is interesting because it has been shown that lymphoma cells have a particularly high expression level of ATX [32]. However, there was no significant difference between serum ATX levels in Hodgkin's patients with or without pruritus [25]. The reason for this may be that local ATX release as may occur from lymphomas has much less effect on systemic ATX levels than on a systemic condition like cholestasis. Nakao et al. [37] recently reported elevated serum ATX activity and protein levels in patients with atopic dermatitis. Moreover, it was shown that the level of serum ATX in these patients correlated not only with the severity of the disease but also with itch intensity [37]. Shimizu et al. [45] also found increased ATX activity in serum samples from such a patient group but claimed that this is due to decreased presence of an, as yet unidentified, inhibitory factor. However, in a mouse model of atopic dermatitis, the so called Naruto Research Institute Otsuka Atrichia mouse (NOA), this group [44] reported that blood ATX levels were increased compared to control mice, but that most of the ATX protein was associated with the cellular fraction. The authors hypothesized that LPA, carried by blood cells, may act at different levels in the skin, i.e. by causing hyperpermeability of the endothelium and allowing LPA to enter the
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local tissue, by stimulating local entry of lymphocytes and by direct action as a pruritogen. In conclusion, it appears that LPA signaling plays an important role in various pathological states through signaling in sensory neurons. However, many aspects on the mechanisms by which this takes place need to be further clarified. In neuropathic pain it has not been sorted out yet how LPA signaling relates to many changes in channel function and neuropeptide secretion that have been reported in neuropathic pain. It is also still quite unclear whether LPA plays a primary role in the induction of pruritus under cholestatic conditions and it remains to be shown what the trigger is that induces autotaxin levels in blood during cholestasis. Acknowledgement This research was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, Top grant # 91210054). References [1] D.K. Ahn, S.Y. Lee, S.R. Han, J.S. Ju, G.Y. Yang, M.K. Lee, D.H. Youn, Y.C. Bae, Intratrigeminal ganglionic injection of LPA causes neuropathic pain-like behavior and demyelination in rats, Pain 146 (2009) 114–120. [2] T. Akiyama, E. Carstens, Neural processing of itch, Neuroscience 250 (2013) 697–714. [3] F. Alemi, E. Kwon, D.P. Poole, T. Lieu, V. Lyo, F. Cattaruzza, F. Cevikbas, M. Steinhoff, R. Nassini, S. Materazzi, R. Guerrero-Alba, E. Valdez-Morales, G.S. Cottrell, K. Schoonjans, P. Geppetti, S.J. Vanner, N.W. Bunnett, C.U. Corvera, The TGR5 receptor mediates bile acid-induced itch and analgesia, J. Clin. Invest. 123 (2013) 1513–1530. [4] K. Bandoh, J. Aoki, A. Taira, M. Tsujimoto, H. Arai, K. Inoue, Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species. Structure–activity relationship of cloned LPA receptors, FEBS Lett. 478 (2000) 159–165. [5] T.C. Bartholomew, J.A. Summerfield, B.H. Billing, A.M. Lawson, K.D. Setchell, Bile acid profiles of human serum and skin interstitial fluid and their relationship to pruritus studied by gas chromatography–mass spectrometry, Clin. Sci. (Lond.) 63 (1982) 65–73. [6] D.M. Bautista, S.R. Wilson, M.A. Hoon, Why we scratch an itch: the molecules, cells and circuits of itch, Nat. Neurosci. 17 (2014) 175–182. [7] N.V. Bergasa, S.L. Sabol, W.S. Young III, D.E. Kleiner, E.A. Jones, Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver, Am. J. Physiol. 268 (1995) G346–G354. [8] U. Beuers, A.E. Kremer, R. Bolier, R.P. Oudeelferink, Pruritus in cholestasis — facts and fiction, Hepatology 60 (2014) 399–407. [9] Z. Callaerts-Vegh, S. Leo, B. Vermaercke, T. Meert, R. D'Hooge, LPA(5) receptor plays a role in pain sensitivity, emotional exploration and reversal learning, Genes Brain Behav. 11 (2012) 1009–1019. [10] J. Chemin, A. Patel, F. Duprat, M. Zanzouri, M. Lazdunski, E. Honore, Lysophosphatidic acid-operated K + channels, J. Biol. Chem. 280 (2005) 4415–4421. [11] S.C. Chia, N.V. Bergasa, D.E. Kleiner, Z. Goodman, J.H. Hoofnagle, A.M. Di Bisceglie, Pruritus as a presenting symptom of chronic hepatitis C, Dig. Dis. Sci. 43 (1998) 2177–2183. [12] J.W. Choi, J. Chun, Lysophospholipids and their receptors in the central nervous system, Biochim. Biophys. Acta 1831 (2013) 20–32. [13] M.R. Freedman, R.T. Holzbach, D.R. Ferguson, Pruritus in cholestasis: no direct causative role for bile acid retention, Am. J. Med. 70 (1981) 1011–1016. [14] V. Geenes, C. Williamson, Intrahepatic cholestasis of pregnancy, World J. Gastroenterol. 15 (2009) 2049–2066. [15] A. Giganti, M. Rodriguez, B. Fould, N. Moulharat, F. Coge, P. Chomarat, J.P. Galizzi, P. Valet, J.S. Saulnier-Blache, J.A. Boutin, G. Ferry, Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization, J. Biol. Chem. 283 (2008) 7776–7789. [16] T. Hashimoto, H. Ohata, K. Momose, Itch-scratch responses induced by lysophosphatidic acid in mice, Pharmacology 72 (2004) 51–56. [17] M. Inoue, L. Ma, J. Aoki, J. Chun, H. Ueda, Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain, Mol. Pain 4 (2008) 6. [18] M. Inoue, L. Ma, J. Aoki, H. Ueda, Simultaneous stimulation of spinal NK1 and NMDA receptors produces LPC which undergoes ATX-mediated conversion to LPA, an initiator of neuropathic pain, J. Neurochem. 107 (2008) 1556–1565. [19] M. Inoue, M.H. Rashid, R. Fujita, J.J. Contos, J. Chun, H. Ueda, Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004) 712–718. [20] E.A. Jones, N.V. Bergasa, The pruritus of cholestasis: from bile acids to opiate agonists, Hepatology 11 (1990) 884–887. [21] A. Kazantseva, A. Goltsov, R. Zinchenko, A.P. Grigorenko, A.V. Abrukova, Y.K. Moliaka, A.G. Kirillov, Z. Guo, S. Lyle, E.K. Ginter, E.I. Rogaev, Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH, Science 314 (2006) 982–985.
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Review
Lysophosphatidic acid and signaling in sensory neurons☆ Ronald P.J. Oude Elferink ⁎, Ruth Bolier, Ulrich H. Beuers Tytgat Institute for Liver and Intestinal Research, Academic Medical Center Amsterdam, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 30 May 2014 Received in revised form 22 August 2014 Accepted 5 September 2014 Available online 16 September 2014 Keywords: Lysophosphatidic acid Autotaxin Cholestasis Pruritus Neuropathic pain
a b s t r a c t Lysophosphatidic acid is a potent signaling lipid molecule that has initially been characterized as a growth factor. However, later studies have revealed many more functions such as modulation of cell shape, cell migration, prevention of apoptosis, platelet aggregation, wound healing, osteoclast differentiation, vasopressor activity, embryo implantation, angiogenesis, lung fibrosis, hair growth and more. The molecule mainly acts through the activation of a set of at least 6 G-protein-coupled receptors (LPA1–6), but intracellular LPA was also shown to signal through the activation of the nuclear receptor PPARγ. In this short review we discuss the recent observations which suggest that in pathological conditions LPA also modulates signaling in sensory neurons. Thus, LPA has been shown to play a role in the initiation of neuropathic pain and, more recently, a relation was observed between increased LPA levels in the circulation and cholestatic itch. The mechanism by which this occurs remains to be elucidated. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. © 2014 Elsevier B.V. All rights reserved.
1. LPA synthesis Lysophosphatidic acid is a phospholipid metabolite that can be generated by different intra- and extracellular pathways. The intracellular pathway can start by the generation of phosphatidic acid from phospholipid by phospholipase D. It can also be generated by the acylation of glycerophosphate by glycerophosphate acyltransferase or by the phosphorylation of diacylglycerol by diacylglycerol kinase (DGK). The subsequent action of PLA1 or PLA2 then generates LPA with the fatty acyl chain on the sn2 or sn1 position, respectively. The fact that LPA often bears an unsaturated acyl chain shows that PLA1 should be involved because the sn2 position does not generally have a saturated acyl chain whereas the sn1 position does. The family of PLA1 enzymes has not been very extensively studied, however. One PLA1 deserves particular interest as it seems to have a specific role in LPA signaling in hair follicle stimulation. Two genes have been identified to play a causative role in hair growth deficiency. One is the lipase H (LIPH) gene that when mutated gives rise to hypotrichosis and wooly hair [21]. Lipase H is a phospholipase A1 expressed in hair follicles. This enzyme is localized in the plasma membrane and has preference for phosphatidic acid (within the membrane) as a substrate. In addition, mutations in the gene encoding the LPA6 (P2Y5) receptor give rise to the same phenotype [41,46]. Hence, it is very likely that these two proteins function in the same pathway of regulation of hair growth.
☆ This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. ⁎ Corresponding author. Tel.: +31 20 5663828; fax: +31 20 5669190. E-mail address: [email protected] (R.P.J. Oude Elferink).
http://dx.doi.org/10.1016/j.bbalip.2014.09.004 1388-1981/© 2014 Elsevier B.V. All rights reserved.
Most of the signaling functions of LPA occur through binding to LPAspecific G-protein coupled receptors and thereby involve extracellular levels of LPA. However, there are also intracellular functions. LPA has been characterized as an activating ligand of the nuclear receptor PPARγ [33,47], which is particularly involved in the regulation of energy metabolism and adipogenesis. In addition, it has recently been shown that intracellular LPA is able to directly stimulate the transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a nonselective cation channel that functions as an integrator of signals in sensory neurons (see below). Other channels have also been reported as targets of intracellular LPA [10]. The production of blood-borne LPA starts with the action of secretory PLA1 or PLA2 or by lecithin-cholesterol acyltransferase. All these reactions produce lysophospholipid which can subsequently be converted to LPA by the enzyme autotaxin. Autotaxin is a phospholipase D in blood that is secreted by various cell types such as the adipose tissue, choroid plexus, kidney, and lung intestine [15]. Although ATX was originally thought to be a membrane-associated enzyme, it has become clear that it is secreted into blood where it converts lysophospholipid into LPA. However, the enzyme binds to target cells via integrin and heparan sulfate proteoglycans. Binding to heparin sulfate is mediated by the exon 12-encoded polybasic insert that is only present in the alternatively spliced isoform ATX-α. In contrast, all ATX isoforms bind to β1 and β3 integrins via the second of two somatomedin B binding (SMB) motifs in the N-terminal part of all isoforms of the protein. This integrin-mediated binding is thought to play an important role in the delivery of LPA to LPA receptors on target cells. Crystallography of the protein has revealed a tunnel in the protein which has been suggested to function as an LPA exit channel allowing the delivery of LPA to its cognate receptors [36,39].
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2. LPA receptors At present 6 receptors have been recognized to be responsive to LPA. The classical receptors (LPA1, LPA2 and LPA3) were earlier designated as Edg (endothelial differentiation gene) receptors. All six receptors are G-protein coupled receptors, but their intracellular signaling pathways differ. Thus, LPA1, LPA2 and LPA4 relay to Gα12/13, Gαq/11 and Gαi/o isoforms, whereas LPA3 relays to Gαq/11 and Gαi/o and LPA5 relays to Gα12/13 and Gαq/11. LPA6 relays to Gα12/13 and Gαi/o. Importantly, LPA4 and LPA6 also relay to Gαs, which through its induction rather than the reduction of cAMP may give rise to opposite effects. In this way, and depending on cell-specific expression of the different LPA receptors, a quite diverse scala of signaling functions may be achieved. As an example, LPA4 was found to have opposite effects compared to LPA1-3 in terms of cell motility [26] and osteoblast differentiation [29]. There are differences in the specificities of the receptors for various forms of LPA [4]. All LPA receptors have the highest reactivity with LPA containing oleic (18:1), linoleic (18:2), or linolenic (18:3) followed by palmitoleoyl (16:1) and arachidonoyl (20:4) LPA. In contrast to LPA1 and LPA3, LPA2 is also well activated by myristoyl (14:0) and palmitoyl (16:0) LPA. Interestingly, LPA6 appears to have a preference for LPA with the fatty acyl chain on the sn2 position in contrast to the other receptors that are more or less equally activated by LPA molecules with the fatty acyl chain in the sn1 or sn2 position [52]. This fits with the fact that LPA6 (P2Y5) is thought to be activated by LPA generated by Lipase H, which is a phospholipase A1 [41,46]. LPA1-6 receptors are expressed at varying levels in the CNS during development and postnatal life [12]. In neurons LPA1 and LPA2 are expressed with the latter more abundantly [40]. LPA5 is also expressed in sensory and motor neurons in the spinal cord and appears to have a functional role in pain processing. Astrocytes express LPA1-5 whereas oligodendrocytes express LPA1 and LPA2 [12]. Also in peripheral sensory neurons the expression of LPA receptors has been reported, although the identification of subsets of LPA-responsive sensory neurons (such as in different fiber types as well as pain vs. itch) is incomplete yet. 3. The role of LPA in neuropathic pain Neuropathic pain is defined as ‘Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ [30]. It is a form of chronic pain that is not caused though stimulation of sensory neurons by “physiological” pain stimuli but rather by dysfunction or injury of the fibers. This dysfunction is a consequence of underlying diseases such as (among others) diabetes, cancer and multiple sclerosis. Injury may have taken place at different levels: central (such as in spinal cord injury or brain infarction) or peripheral (due to systemic diseases or ischemic neuropathy). Multiple and diverse mechanisms have been identified for the development of neuropathic pain, including peripheral sensitization, structural reorganization, demyelination and central sensitization. Together these events lead to alteration in the production of neuropeptides and their cognate receptors and function of ion channels. Among many processes that have been described to play a role in neuropathic pain, an extensive body of work also points to a role for LPA signaling. It was shown in 2004 by the group of Ueda that the initiation of neuropathic pain requires LPA signaling [19]. For research purposes, a frequently used animal model for neuropathic pain is partial sciatic nerve injury which causes prominent allodynia (pain perception upon an otherwise unpainful stimulus) and hyperalgesia that last for at least two weeks. In mice, allodynia and hyperalgesia are monitored by the paw pressure test and the tail flick test. Applying this model to mice, Inoue et al. [19] found that pain perception was strongly reduced in LPA1 knockout mice but not in LPA2 knockout mice. Conversely, intrathecal injection of LPA caused hyperalgesia and allodynia that lasted for about 7 days. In wild type mice LPA injection was accompanied by demyelination of dorsal root fibers, a phenomenon that is observed with neuropathic pain. In LPA1−/− mice this demyelination was
reduced. Demyelination reduces the isolation of the fibers so that action potentials generated in one axon can lead to membrane potential changes in adjacent axons that put them closer to threshold, perhaps even causing an ectopic action potential. It was hypothesized that LPA at high concentrations is generated at the site of the wound by activated platelets, degenerating axons and/or damaged neurons and that LPA1 receptors, also present on Schwann cells, mediate demyelination. Similar results were reported by Ahn et al. [1] using the model of LPA injection in the trigeminal ganglia of rats. Subsequently, Inoue et al. [17] showed that partial sciatic nerve injury caused reduced hyperalgesia in Atx+/− mice, suggesting that ATX is involved in the generation of LPA during nerve injury. This experiment cannot be performed in a full Atx knockout as these animals are not viable [50]. Inoue et al. also observed that overstimulation of pain fibers by the treatment of spinal cord slices with capsaicin (10 μM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, caused production of LPA. LPA was also induced by combination treatment of slices with high doses (10 and 30 μM) of substance P and NMDA in the presence of recombinant autotaxin. These observations suggested that the overstimulation of fibers leads to increased production of LPC the substrate from which ATX produces LPA, but this was not directly measured [18]. More recently, data were provided which demonstrated that LPA release causes a feed-forward LPA production in the early phase of neuropathic pain by the activation of the LPA3 receptor [31]. It was speculated that nerve injury may induce the production of LPA at the early phase and subsequently cause LPA1 receptor activation to induce neuropathic pain. The mechanism of demyelination upon LPA release was further investigated and seems to involve calpaindependent downregulation of myelin-associated protein (MAG) [51] in dorsal roots. Recently, the group of Chun implicated yet another LPA receptor, LPA5, in the mechanism of initiation of neuropathic pain [27]. LPA5 mRNA was detected in a subset of DRG neurons. LPA5 was also expressed in the dorsal horn area of the lumbar spinal cord, and as expected, signal transduction was absent in these tissues in LPA5deficient mice. Interestingly, normal pain sensation was not altered in LPA5-deficient mice, whereas the development of nerve injuryinduced neuropathic pain (partial sciatic nerve ligation) was abolished. This protection was accompanied by the downregulation of phosphorylated cAMP response element binding protein (pCREB) signaling in spinal cord dorsal horn neurons. In contrast to what was observed in LPA1−/− mice, the LPA5 loss did not prevent demyelination indicating that LPA5 signals through another pathway. While this study did not find a difference in normal pain perception in LPA5−/− mice, Callaerts-Vegh et al. [9] did report reduced nociception in Freund's adjuvant-induced inflammatory pain in these animals.
4. The role of LPA in (cholestatic) itch Itch is defined as the sensation that urges to scratch and is induced by a host of endogenous and exogenous compounds. It can have a great variety of causes from skin diseases to cancer and systemic diseases but it can also be psychogenic. Until about 15 years ago it was thought that itch is mediated through the same fibers as pain, but that itch sensation is caused by subliminal activation of pain neurons. However, the present paradigm is that itch is mediated by separate fibers from (inflammatory) pain although the two are transduced by very similar small diameter C-fibers with unmyelinated nerve endings [2,6]. Thus, the activation of both itch and pain neurons requires the function of the non-specific cation channel TRPV1. The theory of separate itch fibers is supported by the observation of specific neurotransmitters for itch (gastrin-releasing peptide [48] and natriuretic peptide B [35]). Conversely, there is a clear interaction between itch and pain, because at the spinal level pain signals suppress itch signaling through interneurons. The transcription factor Bhlhb5 is transiently expressed in the dorsal
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horn of the developing spinal cord to regulate a unique population of inhibitory interneurons that inhibit itch [43]. Pruritus is a frequent symptom in many hepatobiliary disorders, particularly those with cholestatic features [8,28]. This form of itching is designated cholestatic pruritus as bile secretion and/or flow is impaired in these disorders. Cholestatic pruritus may be caused by impaired hepatocellular secretory function as seen in intrahepatic cholestasis of pregnancy (ICP), benign recurrent intrahepatic cholestasis (BRIC), progressive familial intrahepatic cholestasis (PFIC), toxin- or druginduced cholestasis, and chronic viral hepatitis B and C infections. It may also occur upon intrahepatic bile duct damage and secondary hepatocyte secretory failure as in primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and pediatric cholestatic syndromes such as the Alagille syndrome. Finally, cholestasis due to the obstruction of the intrahepatic or extrahepatic bile duct draining system is observed in cholestasis caused by gallstones, PSC, cholangiocellular carcinoma, obstructive tumors of the pancreatic head or enlarged lymph nodes located in the hilar region, bile duct adenomas, or biliary atresia. Interestingly, the prevalence of pruritus varies considerably between these disorders. Pruritus is the defining symptom of women suffering from ICP [14] and is experienced by a large proportion of patients with PBC and PSC. In contrast, pruritus is less frequently reported by patients with obstructive cholestasis [34] and chronic hepatitis C infections [11], and rarely associated with chronic hepatitis B patients, non-alcoholic fatty liver disease, and alcoholic or nonalcoholic steatohepatitis even when cholestasis is present [23]. In various cholestatic disorders such as PBC and ICP it is an early symptom that can even be experienced before the diagnosis of cholestasis. Although chronic pruritus is a very distressing symptom, the cause of cholestatic itch has been unclear for a long time and still is poorly understood. The general working hypothesis is that compounds that accumulate in blood during cholestasis are normally efficiently secreted into bile. Besides useful compounds like bile salts, also many toxins and endogenous waste products are secreted into bile either or not after being metabolized and/or conjugated with various groups like glucuronic acid sulfate and glutathione. Many of these compounds are reabsorbed in the intestine after deconjugation and in this way undergo enterohepatic circulation. Originally, it was hypothesized that during cholestasis bile salts accumulate in the circulation cause itch. Indeed it has been observed that bile salts are capable to induce in vitro mast cell degranulation [42]. However, this occurs at bile salt concentrations that are well above those at which cholestatic itch is observed. Furthermore, a relation between serum bile salt levels and the extent of itch has never been established [5,13]. Interestingly, the group of Corvera [3] recently postulated that the G protein-coupled receptor TGR5, which is activated by bile salts and neurosteroids, may play a role in the generation of cholestatic itch. They showed that TGR5 is expressed on neurons in the dorsal root ganglia of mice and this expression partially overlaps with TRPV1 and GRP, suggesting that TGR5 is expressed on itchselective sensory neurons. In vivo experiments in TGR5 overexpressing mice revealed an increased basal scratch activity and intradermal injection of deoxycholate (DCA) evoked scratch behavior in wild type mice, that was partly reduced in TGR5−/− mice and increased in TGR5-overexpressing mice. These findings would support a primary role for TGR5 in itch induction. Unfortunately, for most of the in vitro experiments relatively high concentrations of unconjugated DCA (up to 100 μM) were used. Again, these concentrations are much higher than those observed in pathological conditions, like PBC and ICP, associated with itch. A second hypothesis has been that during cholestasis endogenous opioids are increased which would decrease pain perception and thereby increase itch [20]. It was indeed found that cholestasis in rats leads to increased serum levels of enkephalins as well as increased mRNA levels of preproenkephalin in the liver [7,49]. However, although increased
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levels of serum μ-opioid can be observed in some cholestatic patients there is no relation between these levels and the extent of itch [24]. More recently, Kremer et al. [24] have performed a screen for compounds in cholestatic serum that activate neuronal cells with the aim to identify a new “itch factor”. This screen revealed increased levels of LPA in sera from women with intrahepatic cholestasis of pregnancy (ICP) as well as patients with primary biliary cirrhosis (PBC) that had itch. The increased levels of LPA correlated with highly significant increases in serum autotaxin (ATX) levels and the latter even correlated with the severity of itch. In a later report it was demonstrated that effective therapy for cholestatic itch, such as biliary diversion and rifampicin treatment, led to significant decrease of serum ATX [25]. It was also shown that ATX expression in HepG2 cells could be downregulated by treatment with rifampicin and that this involved the activation of the nuclear receptor PXR [25]. Finally, it has been reported that intradermal injection of LPA in mice leads to significant and dose-dependent scratch behavior [16,22,44]. Shimizu et al. [44] showed, in addition, that this scratch behavior could be inhibited by the administration of the LPA1 and LPA3 receptor antagonists Ki16425. Hashimoto et al. [16] demonstrated that the administration of ketotifen, a mast cell stabilizer, also diminished LPA-induced scratch behavior, suggesting that it occurs through mast cell degranulation. These data suggest that there may be a causative role for ATX-mediated LPA production in the activation of itch neurons. It remains to be further investigated whether this occurs primarily through mast cell activation or also through direct activation of LPA receptors on itch neurons. This is particularly important as cholestatic itch is refractory to antihistamines [23]. It is of note that LPA is also capable of directly activating the nonselective cation channel TRPV1 that is involved in generation of action potentials in sensory neurons [38]. It was demonstrated in patch clamp studies, that LPA stimulates TRPV1 channel opening but does so considerably faster and stronger in inside-out membrane patches (i.e. intracellular signaling) than in right side out patches (i.e. extracellular signaling). LPA seems to interact with a proposed intracellular PIP2 binding site on TRPV1 in which the lysine 710 residue participates. Thus, this report suggests a role for intracellular rather than extracellular LPA. Since LPA is a relatively hydrophilic lipid molecule, that will not passively cross the plasma membrane of cells, it remains to be shown how relevant this type of activation is with regard to extracellularly generated LPA. 5. Autotaxin and other conditions of chronic itch Kremer et al. [25] demonstrated that serum autotaxin levels not only are elevated in cholestasis but also are significantly increased, albeit to a much lesser extent, in serum from patients with atopic dermatitis and in patients with Hodgkin's disease. The latter aspect is interesting because it has been shown that lymphoma cells have a particularly high expression level of ATX [32]. However, there was no significant difference between serum ATX levels in Hodgkin's patients with or without pruritus [25]. The reason for this may be that local ATX release as may occur from lymphomas has much less effect on systemic ATX levels than on a systemic condition like cholestasis. Nakao et al. [37] recently reported elevated serum ATX activity and protein levels in patients with atopic dermatitis. Moreover, it was shown that the level of serum ATX in these patients correlated not only with the severity of the disease but also with itch intensity [37]. Shimizu et al. [45] also found increased ATX activity in serum samples from such a patient group but claimed that this is due to decreased presence of an, as yet unidentified, inhibitory factor. However, in a mouse model of atopic dermatitis, the so called Naruto Research Institute Otsuka Atrichia mouse (NOA), this group [44] reported that blood ATX levels were increased compared to control mice, but that most of the ATX protein was associated with the cellular fraction. The authors hypothesized that LPA, carried by blood cells, may act at different levels in the skin, i.e. by causing hyperpermeability of the endothelium and allowing LPA to enter the
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