TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of “forefront” signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.
Introduction
Itch is a clinical problem that leaves many sufferers insufficiently treated, with >20 million in the United States (
1.
, 2.
, 3.
). This is also caused by incomplete understanding of its molecular, cellular, and cell-to-cell signaling mechanisms. Neural pathways have been understood as key for itch, whereby specialized primary sensory pruriceptor neurons relay sensory afferent information to itch-transmitting neural pathways, ultimately evoking the sensation of itch (2.
, 4.
, 5.
, 6.
, 7.
, 8.
). Exogenous or endogenous pruritogens are thought to act on primary sensory neurons, producing the sensation of itch by activating the pruriceptors expressed by these afferents. Primary pruriceptor neurons may receive modulatory signals from atopic inflammatory cells, such as mast cells, and also from epidermal keratinocytes (7.
). It was recently elucidated that the atopia cytokine, thymic stromal lymphopoietin (TSLP), was secreted from skin keratinocytes to activate TRPA1 ion channels on primary pruriceptor neurons and induced itch (9.
). Despite this landmark discovery, mechanisms of how the epidermal keratinocyte specifically functions to evoke itch remain largely unknown, especially mechanistic insights that rely on precise genetic targeting of genes-of-interest only in keratinocytes. In other words, molecular and cell-to-cell signaling mechanisms of forefront pruri-transduction are elusive.We recently defined a mechanism of how ultraviolet B (UVB)
radiation activates TRPV4 ion channels in skin epidermal keratinocytes (
10.
). Their genetically encoded, inducible absence in skin keratinocytes suffices to contain pain and tissue damage evoked by UVB overexposure. In skin keratinocytes, TRPV4 activation by UVB is potentiated by endothelin-1 (ET-1) via endothelin receptors A and B. TRPV4-activation in these cells leads to Ca2+ influx, which in turn increases gene expression of ET-1, providing the substrate of a feed-forward mechanism that sustains organismal pain. This is an interesting observation in the context of itch because ET-1 injection into skin is known to cause itch in human subjects and evokes scratching behavior in experimental animals upon intradermal injection (- Moore C.
- Cevikbas F.
- Pasolli H.A.
- Chen Y.
- Kong W.
- Kempkes C.
- Parekh P.
- Lee S.H.
- Kontchou N.A.
- Yeh I.
- Ye I.
- Jokerst N.M.
- Fuchs E.
- Steinhoff M.
- Liedtke W.B.
UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling.
Proc. Natl. Acad. Sci. U.S.A. 2013; 110: E3225-E3234
11.
, 12.
, 13.
, 14.
, 15.
, 16.
). TRPV4 has been implicated in other forms of pain (10.
, - Moore C.
- Cevikbas F.
- Pasolli H.A.
- Chen Y.
- Kong W.
- Kempkes C.
- Parekh P.
- Lee S.H.
- Kontchou N.A.
- Yeh I.
- Ye I.
- Jokerst N.M.
- Fuchs E.
- Steinhoff M.
- Liedtke W.B.
UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling.
Proc. Natl. Acad. Sci. U.S.A. 2013; 110: E3225-E3234
17.
, 18.
, 19.
, - Grant A.D.
- Cottrell G.S.
- Amadesi S.
- Trevisani M.
- Nicoletti P.
- Materazzi S.
- Altier C.
- Cenac N.
- Zamponi G.W.
- Bautista-Cruz F.
- Lopez C.B.
- Joseph E.K.
- Levine J.D.
- Liedtke W.
- Vanner S.
- Vergnolle N.
- Geppetti P.
- Bunnett N.W.
Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.
J. Physiol. 2007; 578: 715-733
20.
, 21.
, 22.
, 23.
, - Zhao P.
- Lieu T.
- Barlow N.
- Metcalf M.
- Veldhuis N.A.
- Jensen D.D.
- Kocan M.
- Sostegni S.
- Haerteis S.
- Baraznenok V.
- Henderson I.
- Lindström E.
- Guerrero-Alba R.
- Valdez-Morales E.E.
- Liedtke W.
- McIntyre P.
- Vanner S.J.
- Korbmacher C.
- Bunnett N.W.
Cathepsin S causes inflammatory pain via biased agonism of PAR2 and TRPV4.
J. Biol. Chem. 2014; 289: 27215-27234
24.
, 25.
, 26.
). It is a multimodally activated TRPV channel, e.g. activated by changes in osmotic pressure, mechanical, UVB, and chemical cues and modified by thermal cues (27.
, 28.
, 29.
, 30.
, 31.
). Except for the recent elucidation of the role of TRPV4 as ionotropic receptor for UVB in keratinocytes to reprogram these cells into organismal pain generators, its role in pain has been attributed to its expression in primary sensory neurons.Against this background, especially the finding of TRPV4-dependent secretion of the pruritogen, ET-1, by keratinocytes, we felt that we have raised a timely question, namely whether TRPV4 plays a role in itch, in particular whether TRPV4 in keratinocytes of the epidermis can drive scratching behavior. To address this question we decided to first focus on acute itch and, specifically, as an initial priority, to examine prototypic examples of histaminergic itch, including ET-1-evoked itch, plus chloroquine-caused non-histaminergic itch. In this study we are reporting an exciting new function of TRPV4 in forefront signaling of the integument, namely that TRPV4 in epidermal keratinocytes functions as a pruriceptor-TRP channel in acute histaminergic itch, including itch evoked by ET-1, not in non-histaminergic itch evoked by chloroquine. Direct activation of TRPV4 channels also evokes scratching behavior, which appears completely dependent on TRPV4 expression in keratinocytes, thus underscoring the role of this cell and its expression of TRPV4 in itch. Complementing findings in our Trpv4 keratinocyte-specific inducible knock-out (Trpv4 cKO) mice, we demonstrate Ca2+ transients in response to histaminergic pruritogens in cultured primary keratinocytes that depend on TRPV4. Ca2+ influx via TRPV4 then up-regulates phosphorylation of the mitogen-activated protein kinase ERK in keratinocytes. Consequently, we find topical transdermal treatment with a selective inhibitor of TRPV4 to function efficiently as an anti-pruritogen. Moreover, we observed similar in vivo anti-pruritic effects when topically targeting MEK, upstream of ERK, with a selective inhibitor.
Discussion
In this study we describe a novel role for TRPV4 channels in histaminergic itch including ET-1-evoked itch. Importantly, TRPV4 expression and function in epidermal keratinocytes shows a robust contributory role to scratching behavior evoked by histaminergic pruritogens, not for the non-histaminergic chloroquine. This means that keratinocytes of the integument can function as itch generator cells and that TRPV4 plays a significant signaling role in these cells in mediating histaminergic itch. Importantly, direct activation of TRPV4 by intra-dermal injection of TRPV4 activator, GSK101, led to scratching behavior, which critically depended on TRPV4 expression in keratinocytes. This finding underscores the fundamental, hitherto unrecognized role of TRPV4 channels in epidermal keratinocytes in acute histaminergic itch. We recorded complementary findings in primary keratinocyte culture where we observed Ca2+ transients in response to the same diverse histaminergic pruritogens that elicit scratching behavior dependent on keratinocyte-TRPV4. We found this Ca2+ response to be mediated by TRPV4, which was activated by the respective pruritogens and their cognate keratinocyte-G protein-coupled receptors or directly via selective chemical activator. In epidermal keratinocytes, Ca2+ influx via TRPV4 elicits ERK phosphorylation as a downstream signaling event of the forefront pruritogen signaling discovered here. Topical transdermal inhibition of TRPV4 and its downstream kinase target, MEK, which functions upstream of ERK phosphorylation, both showed robust anti-pruritic efficiency in mice challenged with histaminergic pruritogens. Activation of MEK-ERK signaling in keratinocytes is also known from non-itching skin conditions (
53.
, 54.
). We speculate that MEK-ERK activation by TRPV4 could be the important explanatory difference. This hypothetic concept will have to be tested in future studies. Our results argue for a novel translational medical path of topical treatments to skin that target molecularly defined signaling mechanisms that modulate sensory transduction (- Einspahr J.G.
- Calvert V.
- Alberts D.S.
- Curiel-Lewandrowski C.
- Warneke J.
- Krouse R.
- Stratton S.P.
- Liotta L.
- Longo C.
- Pellacani G.
- Prasad A.
- Sagerman P.
- Bermudez Y.
- Deng J.
- Bowden G.T.
- Petricoin 3rd, E.F.
Functional protein pathway activation mapping of the progression of normal skin to squamous cell carcinoma.
Cancer Prev. Res. (Phila). 2012; 5: 403-413
55.
).- Baumbauer K.M.
- DeBerry J.J.
- Adelman P.C.
- Miller R.H.
- Hachisuka J.
- Lee K.H.
- Ross S.E.
- Koerber H.R.
- Davis B.M.
- Albers K.M.
Keratinocytes can modulate and directly initiate nociceptive responses.
Elife. 2015; https://doi.org/10.7554/eLife.09674
In this paper we focus first on acute itch and the role of histaminergic pruritogens. Additional pruritogens need to be studied in the future, with particular focus on chronic itch, a medically relevant condition because of its prevalence and substantial unmet medical need. A central question that we have not addressed in this study is, What specific cellular and molecular mechanisms of cell-to-cell communication do epidermal keratinocytes employ? How does the histaminergic pruritogen-G protein-coupled receptor-TRPV4-Ca2+-pERK pathway evoke these signaling mechanisms, and how does this trigger pruriceptor sensory neurons to transmit the signal toward the nervous system? We hypothesize that soluble factors play such roles, possibly proteins, peptides, small-molecule phospholipids, and lipid molecules that are released from keratinocytes to affect innervating peripheral nerve endings of pruriceptor neurons perhaps either via direct keratinocyte nerve fiber signaling or rather indirectly via involvement of immune, vascular, and other adjacent cells.
A recent study examined the response of spinal cord dorsal horn relay neurons to intradermal injection of ET-1 (
16.
). The study reports that ET-1-sensitive neurons respond to multiple modalities yet that >50% respond to spinal superperfusion of the peptide bombesin, which can activate spinal gastrin-releasing peptide receptors known to function in itch circuits, thus identifying these neurons as part of a specific itch circuit that relies on gastrin-releasing peptide for transmission. When viewing these results together with our current findings, an interesting formation of an ET-1-responsive itch circuit emerges that has its origin with ET-1-responsive keratinocytes that use TRPV4 as critical Ca2+ influx mechanism in response to ET-1 receptor-A activation (10.
). Subsequently these ET-1-responsive keratinocytes activate innervating peripheral sensory neurons, which need to be more precisely defined in future studies, which in turn relay to spinal cord dorsal horn neurons, more than half specifically dedicated to itch-relay via neurotransmission that relies on gastrin-releasing peptide (- Moore C.
- Cevikbas F.
- Pasolli H.A.
- Chen Y.
- Kong W.
- Kempkes C.
- Parekh P.
- Lee S.H.
- Kontchou N.A.
- Yeh I.
- Ye I.
- Jokerst N.M.
- Fuchs E.
- Steinhoff M.
- Liedtke W.B.
UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling.
Proc. Natl. Acad. Sci. U.S.A. 2013; 110: E3225-E3234
16.
).In another recent study from these same authors, Trpv4 pan-null mice were reported to scratch less in response to intradermal injection with serotonin (
56.
). The authors report that they did not see different scratch behavior in response to histamine. In this respect, their results differ from our results in Trpv4 pan-null mice. This discrepancy may be related to technical detail such as difference in doses of pruritogen, animal ages, and behavioral assessment methods. Of note, the originating line of mice used is identical between our current and the referenced study. We believe that this seemingly perplexing discrepancy can possibly be resolved in future studies that focus on the influence of genetic background on nocifensive and pruritic behavior and, more importantly, on the impact that epigenetic regulation might play. Of note, different phenotypes of identical lines of Trpv4 pan-null mice, propagated in different laboratories, have been reported previously (57.
, - Ye L.
- Kleiner S.
- Wu J.
- Sah R.
- Gupta R.K.
- Banks A.S.
- Cohen P.
- Khandekar M.J.
- Boström P.
- Mepani R.J.
- Laznik D.
- Kamenecka T.M.
- Song X.
- Liedtke W.
- Mootha V.K.
- Puigserver P.
- Griffin P.R.
- Clapham D.E.
- Spiegelman B.M.
TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis.
Cell. 2012; 151: 96-110
58.
). Importantly, we want to stress that the focus of our present investigation is the distinct contribution of TRPV4 channels in keratinocytes to histaminergic itch, a subject of basic science and translational-medical relevance that is not directly approached in Akiyama et al. (56.
).With TRPV4 expression in the primary sensory neuron and in the CNS in neurons and glial cells established, which roles do neural and neuronal TRPV4 play in itch transduction, transmission, and plasticity? Whereas these questions remain to be answered in future studies, we wish to reiterate the key concept of TRPV4 as forefront pruriceptor TRP channel functioning in epidermal keratinocytes, to drive the organismal scratch response. This concept bears the translational-medical mandate, as mentioned, to develop selective anti-TRPV4 treatments that can be applied topically and that will also have to be inert regarding epidermal cell growth regulation in view of recent findings of attenuated TRPV4 expression in skin epithelial malignancies (
59.
).Pruriceptor-TRPs comprise TRPA1, TRPV1, TRPV3 (
40.
, - Sun S.
- Dong X.
Trp channels and itch.
Semin. Immunopathol. 2015; https://doi.org/10.1007/s00281-015-0530-4
60.
, 61.
, 62.
, 63.
, 64.
, 65.
, 66.
, 67.
, 68.
), and now also TRPV4. Their possible mechanisms of interaction and the respective cellular locale will be attractive subjects for the following chapters in this intriguing story. Possibly, human genetic variation in the respective TRP pruriceptor genes might be relevant for different itch susceptibilities both for physiologic and pathologic forms of itch.Author Contributions
Y. C. and W. B. L. conceived and coordinated the study and analyzed the data. Y. C., Q. F., and Z. W. designed, performed, and analyzed the experiments. J. Y. Z. contributed reagents. Y. C., J. Y. Z., A. S. M., R. P. H., and W. B. L. drafted and revised the article. All authors reviewed the results and approved the final version of the manuscript.
Acknowledgments
We thank Drs. Ru-rong Ji, Fan Wang, and Sidney Simon (all Duke University) for proofreading the manuscript and helpful discussions.
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Article Info
Publication History
Published online: March 09, 2016
Received in revised form:
February 29,
2016
Received:
January 21,
2016
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© 2016 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.
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