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Keratinocytes Can Modulate and Directly Initiate Nociceptive Responses

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Keratinocytes Can Modulate and Directly Initiate Nociceptive Responses 1 Keratinocytes can modulate and directly initiate nociceptive responses 2 Kyle M. Baumbauer*#, Jennifer J. DeBerry*^, Peter C. Adelman*, Richard H. Miller, Junichi 3 Hachisuka, Kuan Hsien Lee, Sarah E. Ross, H. Richard Koerber, Brian M. Davis and Kathryn 4 M. Albers 5 6 University of Pittsburgh School of Medicine, Department of Neurobiology, Pittsburgh Center for 7 Pain Research, Center for Neuroscience at the University of Pittsburgh 8 9 10 Correspondence to: 11 Kathryn M. Albers, Ph.D. 12 University of Pittsburgh School of Medicine 13 200 Lothrop St. 14 Pittsburgh, PA 15261 15 Email: [email protected] 16 17 * These authors contributed equally to this work. 18 # Present address: University of Connecticut, School of Nursing, Storrs, CT 19 ^ Present address: University of Alabama, Department of Anesthesiology, Birmingham, AL 20 21 Running title: Keratinocytes can initiate cutaneous sensation 22 23 24 25 26 ABSTRACT 27 How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals 28 transmitted by peripheral neurons to the CNS is an area of intense study. Several studies 29 indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal 30 keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin 31 (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce 32 action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A- 33 HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light 34 stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to 35 naturalistic stimuli. These findings support the idea that intrinsic sensory transduction 36 mechanisms in epidermal keratinocytes can direct AP firing in nociceptor as well as tactile 37 sensory afferents and suggest a significantly expanded role for the epidermis in sensory 38 processing. 39 40 41 42 43 44 45 46 47 48 49 2 50 51 52 INTRODUCTION 53 Cutaneous primary sensory afferents are the first in a chain of neurons that convert 54 environmental stimuli into recognizable sensations of touch, heat, cold and pain. Sensory 55 neurons are diverse in nature and exhibit unique chemical, morphological and 56 electrophysiological properties that allow specific responses to applied stimuli. In response to 57 stimuli, the skin produces neuroactive substances that are postulated to directly and indirectly 58 modulate the activity of sensory fibers (1). These substances include glutamate (2, 3), ATP (4- 59 7), acetylcholine (ACh) (8, 9), epinephrine (10, 11), CGRP (12), neurotrophic growth factors 60 (13) and cytokines (14). The skin also expresses ligand-gated (glutamate, ATP, nicotinic, 61 muscarinic, 5-hydroxytryptamine, glycine and gamma-aminobutyric) and voltage-gated 62 (sodium, calcium, transient receptor potential (TRP), potassium and cyclic nucleotide) ion 63 channels and growth factor and cytokine receptors (15). The expression of neuroactivators and 64 voltage and ion-gated channels indicates that complex autocrine and paracrine signaling 65 between epithelial and neural tissues underlie sensory signaling (6, 16-19). 66 67 It has been proposed that non-neuronal cells of the skin, specifically keratinocytes, contribute 68 to the initial transduction process through regulated release of neuroactive substances (4, 6, 69 12, 17, 20). Testing this in an intact system has been difficult because the complexity in skin- 70 nerve interactions prohibits isolation of the skin and neuronal output (a behavioral reflex or the 71 pattern of axonal firing) since any natural stimulation (e.g., mechanical or thermal) 72 simultaneously affects both keratinocytes and sensory neurons. To address this problem, 73 mice with targeted expression of light-activated channelrhodopsin (ChR2) can be used to 3 74 determine the contribution of each cell type to cutaneous associated behavior (withdrawal 75 reflex) and generation of afferent APs. For example, Ji and colleagues (21) showed that blue 76 light stimulation of the skin of transgenic rats that expressed ChR2 in primary afferents under 77 the Thy-1.2 promoter exhibited nocifensive type responses. Similarly, Daou et al (22) showed 78 light-induced behavioral sensitivity in mice in which the Nav1.8 promoter drove expression of 79 ChR2 in a subset of primary afferents. In another optogenetic model, Maksimovic and 80 colleagues directed ChR2 expression to the non-neuronal Merkel cells of the epidermis. Using 81 an ex vivo electrophysiologic preparation they showed that blue light stimulation of the isolated 82 skin elicited AP trains in slowly adapting type 1 (SA1) afferents, thus confirming the essential 83 transducer role of Merkel cells in transmission of mechanical stimuli by SA1 tactile afferents. 84 85 To further examine how the epidermis and cutaneous afferents communicate we analyzed 86 mice in which ChR2 was targeted to either sensory neurons or keratinocytes to determine the 87 contribution of each cell type to cutaneous associated behavior (withdrawal reflex) and 88 generation of afferent APs. Similar to Daou et al (22), we found that light stimulation of the skin 89 and activation of ChR2 in sensory afferents elicits robust nocifensive behaviors in mice. 90 Remarkably, for mice that only express ChR2 in skin keratinocytes, light stimulation was also 91 sufficient to generate nocifensive behaviors and regulate firing properties and evoke APs in 92 specific subsets of cutaneous afferents, several which are known to activate in response to 93 painful stimuli. In addition, expression of the chloride pump NpHR3.0 in keratinocytes 94 significantly reduced AP firing in cutaneous afferents. These data indicate that Merkel cells are 95 not unique in their ability to directly generate action potentials in sensory neurons and that 96 light-mediated activation of keratinocytes is sufficient to engage an endogenous mechanism 97 that can directly regulate cutaneous afferent firing. 98 4 99 100 RESULTS 101 Summary of afferent properties measured using ex vivo intracellular and fiber teasing 102 recordings. 103 In these electrophysiological experiments we have recorded from 200 characterized cutaneous 104 afferents (86 C-fibers, 37 Aδ, 77 Aβ) from the three different mouse genotypes (49 Prph-ChR2, 105 80 KRT-ChR2, 71 KRT-NpHR). The response properties to natural stimuli (pressure, heat, 106 cold) for the different fiber types can be summarized as follows: Aβ-LTMRs had mechanical 107 thresholds from 5-10mN (mean 5.5mN), while Aδ-LTMRs thresholds ranged from1-5mN, with 108 a mean of 2.3mN. For A-HTMRs, Aβ-HTMRs had mechanical thresholds ranging from 10- 109 25mN, with a mean of 17.5mN; Aδ-HTMRs thresholds were 5-100mN, with a mean of 26.7mN. 110 Cutaneous C-fibers showed a range of response properties, with mechanical thresholds from 111 5-50mN (mean 23mN), heat thresholds of 37-50°C (mean 44°C), and cold thresholds of 1- 112 18°C (mean 11°C). No significant differences in these values were observed between 113 genotypes. 114 115 Activation of ChR2 in primary afferents produces nocifensive behaviors and action 116 potentials in multiple types of primary afferents. 117 We first determined the extent to which ChR2 activation in sensory neurons mimicked natural 118 stimulation. Mice harboring a cre-responsive ChR2-YFP fusion gene in the Rosa locus (Ai32 119 mice) were crossed with peripherin (Prph)-cre mice to target ChR2 to unmyelinated and 120 myelinated primary sensory neurons. The YFP tag allowed visualization of ChR2-positive 121 projections in the skin and cell bodies in the dorsal root ganglion (DRG) of Prph-ChR2 mice 122 (Fig. 1A, B). Myelinated and unmyelinated fibers expressed ChR2 as indicated by ChR2-YFP- 123 positive fibers in the skin (Fig. 1A) and physiological recordings (Fig. 1D, E). Behaviorally, all 5 124 Prph-ChR2 mice (5 out of 5 mice tested) demonstrated robust light-induced tail-flick or 125 hindpaw withdrawal in < 30 ms in response to a 473 nm laser light flash, consistent with 126 previous findings (9, 22). Wildtype littermate mice (n=5) were unresponsive. 127 128 We then used an ex vivo skin/nerve/DRG/spinal cord preparation (Fig. 1C)(23, 24) to 129 characterize cutaneous afferent response properties in Prph-ChR2 mice (Fig. 1 D, E). ChR2 130 neurons responded to blue light pulses ranging from 39.7 mW (5-10,000 ms) to 0.7 mW (1000 131 ms pulse). Recordings were made from 49 characterized sensory neurons from 7 mice with 132 26 responders that included 1 A-fiber and 25 C-fiber nociceptors (identified based on their 133 response to noxious mechanical or thermal stimuli) (Table 2). Among laser-responsive C- 134 fibers, 21 responded to mechanical stimuli and of these, 14 responded to heat and/or cold 135 stimuli. Four were classified as responding only to heat stimulation and 7 responded only to 136 mechanical stimuli. 137 138 Activation of Prph-ChR2 afferents revealed complex intrinsic firing properties. A Prph-ChR2 139 Aδ-HTMR (A-delta-high threshold mechanoreceptor) exhibited a tonic response to mechanical 140 stimulation whereas blue light evoked a phasic response (Fig. 1D). In a CMHC nociceptor (C- 141 fiber responding to mechanical, noxious heat and cold stimuli), suprathreshold light stimulation 142 produced tonic firing whereas suprathreshold mechanical stimulation evoked a more phasic 143 response (Fig. 1E). Latency to first response to mechanical and light stimulation was similar. 144 Peak instantaneous frequencies (IF) were significantly higher for suprathreshold mechanical 145 stimulation, averaging 33.9 Hz for mechanical vs 8.6 Hz for light stimulation (@0.7 mW) for all 146 mechanically responsive C-fibers. Interestingly, the average peak IF seen with laser light was 147 similar to that seen in polymodal nociceptors (the majority of cutaneous afferents) in response 6 148 to noxious heat (23, 24). This raised the possibility that afferent-expressed ChR2 activation 149 can evoke a “baseline” response of putative nociceptors that reflects the intrinsic properties of 150 these cells and that more naturalistic responses require collaboration of surrounding cells, 151 including keratinocytes.
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