The Neuroimmune Axis in Skin Sensation, Inflammation, and Immunity Anna M

The Neuroimmune Axis in Skin Sensation, Inflammation, and Immunity Anna M. Trier, Madison R. Mack and Brian S. Kim This information is current as J Immunol 2019; 202:2829-2835; ; of September 24, 2021. doi: 10.4049/jimmunol.1801473 http://www.jimmunol.org/content/202/10/2829 Downloaded from References This article cites 79 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/202/10/2829.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Neuroimmune Axis in Skin Sensation, Inflammation, and Immunity x Anna M. Trier,*,† Madison R. Mack,*,† and Brian S. Kim*,†,‡, Although connections between the immune and ner- branches: one that synapses at the dorsal horn of the spinal cord vous systems have long been recognized, the precise (or brainstem) and another that innervates the peripheral mechanisms that underlie this relationship are just tissue. Its cell body is housed in a peripheral ganglion, either starting to be elucidated. Advances in sensory biology the trigeminal ganglion, if the nerve innervates the face/oral have unveiled novel mechanisms by which inflamma- cavity, or the dorsal root ganglion (DRG), if it innervates tory cytokines promote itch and pain sensations to elsewhere in the body. Itch is sensed following the activation of coordinate host-protective behavioral responses. Con- receptors at peripheral sensory nerve endings in the skin, which versely, new evidence has emphasized the importance ultimately triggers the opening of nonspecific cation channels Downloaded from of immune cell regulation by sensory neurons. By fo- such as transient receptor potential A1 (TRPA1) or TRPV1 cusing on itch biology and how it has been informed by (Fig. 1) (6). The resulting membrane depolarization, if suf- the more established field of pain research, we high- ficient, results in the opening of voltage-gated sodium chan- light recent interdisciplinary studies that demonstrate nels, such as NaV1.7 and NaV1.8, which initiate and propagate the action potential (Fig. 1) (7). These signals are then rapidly how novel neuroimmune interactions underlie a diver- transmitted by the peripheral sensory neuron to the spinal cord, http://www.jimmunol.org/ sity of sensory, inflammatory, and infectious diseases. where neurons of the CNS relay the signal to the brain to evoke The Journal of Immunology, 2019, 202: 2829–2835. sensory perception. Yet, although sensory neurons primarily transmit afferent information from the skin to the CNS, they he skin is one of the first lines of defense against can also release mediators (e.g., neuropeptides) in an efferent chemical,mechanical,microbial,andthermalinsults. manner (such as through an axonal reflex) to communicate T Although the immune system is an essential component with other cell types in the peripheral tissue. of cutaneous immunity, it is increasingly evident that the sensory Delineating the precise identity of skin-innervating neurons nervous system also plays a critical role in host defense. By involved in itch transmission is a highly active area of inves- by guest on September 24, 2021 evoking sensations such as pain and itch, the organism can tigation, as somatosensory neurons are remarkably diverse. immediately sense danger and rapidly initiate a protective be- Traditionally, somatosensory neurons are classified based on havioral response. Additionally, emerging evidence suggests their size, conduction velocity, and degree of myelination. Itch sensory neurons further aid the body’s response to potentially is believed to be largely transmitted by small, unmyelinated, harmful agents by directly modulating immune cell function slow-conducting c-fibers; although thinly myelinated, Ad fi- through the release of mediators such as neuropeptides. In this bers may also play a role (8). Both of these fibers also transmit review, we highlight recent advances in our understanding of pain. Itch was originally believed to be mediated by the same how the sensory nervous system responds to and, in turn, neurons that signaled pain, with the intensity of neuronal regulates the immune system in the setting of cutaneous firing coding which signal is transmitted (9). Indeed, both inflammation and immunity. Specifically, we will focus on itch- and pain-sensory neurons employ many of the same ion itch biology and the studies in pain that helped to inform channels to transmit their signals, including NaV1.7, NaV1.8, this burgeoning field of neuroimmunology (for more TRPA1, and TRPV1 (10). However, through the discovery comprehensive reviews on pain and itch, see Refs. 1–5). of gastrin-releasing peptide receptor (GRPR), Mas-related G protein-coupled receptor (Mrgpr), and the neuropeptide Neurophysiology of itch Nppb, it is now recognized that there are specialized pathways The primary somatosensory neurons that innervate the skin are that can distinctly mediate itch in the periphery (4, 5, 11–14). pseudounipolar, which means that their axons consist of two Currently, the expression of these hallmark receptors and

*Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO Clinical Scientist Development Award, and LEO Pharma. A.M.T. is supported by a grant 63110; †Division of Dermatology, Department of Medicine, Washington University from the National Institute of Allergy and Infectious Diseases at the NIH (T32AI716340). School of Medicine, St. Louis, MO 63110; ‡Department of Anesthesiology, Washington x Address correspondence and reprint requests to Prof. Brian S. Kim, Washington Uni- University School of Medicine, St. Louis, MO 63110; and Department of Pathology and versity School of Medicine, 660 S. Euclid Avenue, P.O. Box 8123, St. Louis, MO Immunology, Washington University School of Medicine, St. Louis, MO 63110 63110. E-mail address: [email protected] ORCID: 0000-0003-2812-0349 (M.R.M.). Abbreviations used in this article: AD, atopic dermatitis; CGRP, calcitonin gene–related Received for publication November 2, 2018. Accepted for publication February 21, peptide; DRG, dorsal root ganglion; ILC2, group 2 innate lymphoid cell; PFT, pore- 2019. forming toxin; SP, substance P; TRPA1, transient receptor potential A1; TSLP, thymic stromal lymphopoietin; VIP, vasoactive intestinal peptide. This work was supported by grants from the National Institute of Arthritis and Musculoskel- etal and Skin Diseases at the National Institutes of Health (NIH; K08AR065577 and Ó R01AR070116), the American Skin Association, a Doris Duke Charitable Foundation Copyright 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801473 2830 BRIEF REVIEWS: THE SKIN NEUROIMMUNE AXIS Downloaded from

FIGURE 1. Neuronal cytokine receptors exhibit specialized functions for pain and itch. Although some ligands, such as histamine, demonstrate significant overlap http://www.jimmunol.org/ in terms of their ability to evoke pain and itch, to date, there appears to be distinct differences between the cytokines that drive pain or itch. Cytokines like IL-1b, IL-6, IL-17A, and TNF-a are predominantly associated with pain responses, whereas cytokines like IL-4, IL-13, IL-31, IL-33, and TSLP are predominantly associated with itch. Following the activation of specific nociceptive or pruriceptive pathways, a number of overlapping cation channels are activated at the neuronal membrane, including TRPA1, TRPV1, Nav1.7, and Nav1.8. IL-1R binds IL-1b; IL-17RA binds IL-17A; gp 130, combines with soluble IL-6R to bind IL-6; TNFR1 binds TNF-a; IL-31RA binds IL-31; IL-4Ra binds IL-4 and IL-13; ST2, the specific subunit of the IL-33 receptor, binds IL-33; TSLP receptor (TSLPR) binds TSLP; TRPA1, transient receptor potential ankyrin 1; and TRPV1, transient receptor potential vanilloid 1; NaV1.7 and NaV1.8, voltage-gated sodium channel 1.7 and 1.8. neuropeptides is used to classify itch-sensory neurons. Recent the hypothesis that the specific sensory response that is evoked studies employing single-cell RNA-sequencing of DRG neu- depends on the type of pathologic insult and the resulting by guest on September 24, 2021 rons have begun to unveil a more comprehensive classification immune response that is generated. of itch-sensory neurons, proposing the existence of a number Building on the initial discovery that IL-1b can induce pain of different subsets (15, 16). However, further work is needed in vivo, a number of studies have identified additional cyto- to assess the in vivo functionality of these subsets and what kines that can also elicit pain by modulating sensory neuronal modalities are distinct, shared, or synergistic. signaling (1). For example, in a rodent model of bone cancer– induced pain, IL-6 was found to critically regulate neuro- Cytokines and itch nal hyperexcitability as well as increased sensitivity to pain The immune response is organized into specialized effector (hyperalgesia) (21). TNF-a was also found to be important in modules that are tailored to combat different types of path- mediating hyperalgesia, specifically in the setting of nerve ogens. Type 1 immunity is broadly used to combat infections injury (22). Finally, in another study, injection of IL-17A was involving intracellular bacteria and viruses and is characterized found to induce pain in the joints of rats in a TNF-a– and by the production of the effector cytokines IFN-g and/or IL-6–independent manner, and treatment with an anti–IL-17 TNF-a. The production of IL-17A and/or IL-22 is a hall- Ab reduced pain symptoms in a model of arthritis indepen- mark of type 3 immunity, which is specialized for extracellular dently of effects on joint swelling (23). Taken together, a bacterial and antifungal defense. Finally, parasitic infections, number of cytokines associated with type 1 and type 3 im- along with noxious environmental substances, result in the mune responses, including IL-1b, IL-6, TNF-a, and IL-17A, generation of a type 2 immune response driven by the pro- have been found to modulate neuronal signaling in various duction of IL-4, IL-5, and IL-13 (17). In addition to coor- models of pain behavior (Fig. 1) (1). However, it is important dinating these specialized immune responses, several cytokines to note that much of the early literature on neuroimmune also modulate sensory perception and behavior, another key regulation of pain is derived from the study of other tissues aspect of host defense (18, 19). The early discovery that the than the skin, such as the bone, joint, and nerve. canonical proinflammatory cytokine IL-1b can induce pain In contrast to pain, which typically involves deeper struc- led to a significant paradigm shift in our understanding of tures, itch is predominantly confined to the skin. Similar to how the immune system participates in sensation and be- pain, a number of different cytokines have been found to havior (20). Subsequently, over the past decade, a number of mediate itch; however, in contrast, the itch-associated cyto- cytokines spanning these specialized immune responses have kines thus far identified are all associated with a type 2 immune been discovered to elicit either pain or itch by directly binding response. Poised to respond to environmental insults, kerati- to their receptors expressed on sensory neurons. This provokes nocytes are key initiators of a host-protective immune response The Journal of Immunology 2831 through the production of alarmins or epithelial cell–derived and promote healing, whereas the scratching response to itch cytokines, such as IL-33 and thymic stromal lymphopoietin sensation may aid in the expulsion of larger ectoparasites and (TSLP). These cytokines potently activate a variety of both noxious environmental substances. innate and adaptive immune cell populations, which results in a robust type 2 immune response characterized by the pro- Acute versus chronic itch duction of IL-4 and IL-13. However, in addition to driving Although acute itch is likely a protective behavioral response, type 2 immunity, it was recently shown that IL-33 and TSLP chronic itch is a highly debilitating medical disorder (37). A can directly activate sensory neurons to evoke itch (24, 25). current focus of the itch field is identifying pruritogens, However, whether these cytokines are the key mediators of molecules that directly activate sensory neurons to induce itch in type 2 inflammatory skin disorders such as atopic itch. A standard technique used to identify such molecules is dermatitis (AD) remains to be clearly defined. Thus, epithe- the injection of a putative pruritogen intradermally into the lial cell–derived cytokines, in response to epidermal stress skin. Potential pruritogens are often injected into the cheek or disruption, have the capacity to simultaneously and rap- skin to allow researchers to distinguish itch from pain be- idly activate both innate immune responses and scratching havior, which are defined as hind limb scratching and front behavior. paw wiping, respectively (38, 39). Although this technique Downstream of IL-33 and TSLP, a number of cell has been extremely valuable in identifying key pruritogens, it populations are elicited to produce IL-4 and/or IL-13, in- is important to note that it is an acute itch model. Scratching cluding basophils, eosinophils, group 2 innate lymphoid cells bouts are evoked within several minutes of introducing the Downloaded from (ILC2s), mast cells, and Th2 cells (26–29). These effector stimulant into the skin and typically last for under an hour. cytokines, in addition to their well-known role in promoting Thus, although it is a very powerful and efficient technique, it barrier inflammation, were recently shown to modulate itch may have potential limitations in defining important media- responses in mice (30). IL-31, which is predominantly pro- tors of chronic itch: when spontaneous scratching commences duced by Th2 cells, also is an important mediator of itch in independently of acute stimuli. These include both genetic vivo (31, 32). However, in contrast to IL-4 and IL-13, IL-31 and chemically induced models of chronic itch conditions, http://www.jimmunol.org/ may not play a prominent role in driving cutaneous inflam- such as allergic contact dermatitis, dry skin, and AD, in which mation. IL-31–deficient mice, in addition to having a re- itch can last from days to weeks (30, 31, 40–42). duction in scratching behavior compared to controls, appear A classic example in which a potent mediator of acute itch to have similar levels of skin inflammation in a model of may not play a key role in driving chronic itch is histamine. contact hypersensitivity (33). In support of this concept, anti– Although histamine is a canonical pruritogen that was used to IL-31RA mAb treatment (nemolizumab) appeared to prefer- validate the intradermal cheek model (38), antihistamines are entially target symptoms of itch rather than inflammation in generally poorly efficacious in many chronic itch disorders,

AD patients in a recent phase 2 clinical trial (34). In contrast, such as AD (43). Conversely, IL-4 and IL-13 are poor acute by guest on September 24, 2021 inhibition of the shared receptor subunit for IL-4 and IL-13 pruritogens, and yet, they are critical drivers of chronic itch in (anti–IL-4Ra mAb [dupilumab]) resulted in a dramatic re- the setting of AD-like disease in mice through their direct duction in both overall disease severity (i.e., cutaneous in- activity on sensory neurons. This appears to be due to the flammation) as well as itch in phase 3 clinical trials for AD ability of these cytokines to sensitize neurons to other pruri- (35). In light of the complex network of cytokines involved in togens like histamine, IL-31, and TSLP (30). Cytokines thus promoting type 2 skin inflammation and itch, futures studies may have additional direct roles in modulating itch beyond will be required to determine how these cytokines come to- the immediate induction of itch signaling. Collectively, these gether to specifically modulate itch in the setting of different studies demonstrate that investigating models of both inflammatory skin disorders. acute and chronic itch are important for providing novel in- Broadly, cytokines that underlie type 1 and/or type 3 im- sight into the biology of itch mediators and their clinical mune responses, such as IL-1b, IL-6, TNF-a, and IL-17A implications. (1, 21–23), have been associated with pain, whereas those associated with a type 2 immune response, such as IL-4, Cytokine signaling in neurons: JAKs IL-13, IL-31, IL-33, and TSLP, involve itch. Additionally, The intracellular signaling pathways downstream of cytokine many diseases associated with type 2 inflammatory features receptor binding on sensory neurons and how they mediate are highly pruritic, such as AD, acute and chronic urticaria, specific sensations is an exciting area of research that is just and prurigo nodularis (36). Although some skin conditions starting to be elucidated. One signaling pathway that was associated with type 1 and/or type 3 immune responses are found to alter neuronal excitability downstream of IL-1b pruritic, such as allergic contact dermatitis, psoriasis, and and TNF-a is phosphorylation of NaV1.8 via p38 MAPK superficial fungal infections, whether effector cytokines spe- (44–46). However, in contrast to the IL-1 and TNF families, cifically associated with these types of immune responses can it is well known that, in immune cells, many cytokine re- act as pruritogens remains poorly defined and is an exciting ceptors use JAKs to activate STAT transcription factors. area of inquiry. However, based on the current body of work Similarly, it appears that neurons use JAKs. For example, JAK in sensory neuroimmunology, we speculate that specialized phosphorylation has been found to be elevated in neurons immune responses specifically evoke the protective behavioral following spinal cord injury in mice (47). However, the response of either pain or itch, depending on the environ- functional significance of JAK signaling in sensory neurons mental stimulus. Pain responses appear to be more commonly was not entirely clear until more recent studies in itch biology. associated with bacteria when aversion to movement may Oetjen et al. (30) demonstrated that neuronal JAK1 is a be needed to minimize the spread of infection (e.g., sepsis) critical mediator of chronic AD–associated itch in vivo. 2832 BRIEF REVIEWS: THE SKIN NEUROIMMUNE AXIS

However, the signaling pathways that are activated in neurons severity (58–60). This improvement may be due to, at least in by JAKs remain poorly defined. In contrast to classical JAK/ part, the loss of IL-23 production from dermal dendritic cells STAT signaling in lymphocytes, it is likely that cytokine- (60). Identifying which neuropeptides critically regulate these mediated stimulation of sensory neurons results in STAT- inflammatory processes is currently a highly active field of independent effects. For example, cytokine stimulation of iso- neuroimmunology. lated DRG neurons by IL-4 and IL-13 results in rapid neuronal Thus far, the neuropeptides substance P (SP) and calcitonin activation, as indicated by a calcium influx within seconds to gene–related peptide (CGRP) have been strongly implicated minutes following cytokine application (30). Given the de- in skin inflammation. Psoriasis-like inflammation in dener- pendence of this calcium response on TRP channels, we vated skin can be restored by intradermal delivery of SP and speculate that JAKs may either directly or indirectly influence CGRP (58). Specifically, SP appears to critically regulate calcium influx into the cell by modulating these channels. How immune cell recruitment, whereas CGRP promotes epidermal this occurs is an exciting area of inquiry. JAKs additionally hyperplasia (acanthosis) in this setting (58). Similarly, in the appear to have long-term effects on the excitability of neurons context of AD, sensory neurons have been shown to regulate such as by altering the expression of TRPA1 and membrane human keratinocyte proliferation in a CGRP-dependent trafficking of TRPV1 (21, 48). These JAK-dependent alter- manner (61). Although CGRP and SP have been the pri- ations in trafficking and transcription may be additional ways mary neuropeptides linked to skin inflammation, additional by which pain and itch sensitization occurs in the periphery and neuropeptides have been found to critically modulate in- how symptoms such as allodynia and alloknesis can develop. flammation at other barrier surfaces, although their role in the Downloaded from Thus, we hypothesize that, in addition to rapidly altering ion skin has yet to be clearly demonstrated. For example, recent channel function through STAT-independent phosphorylation studies have shown that ILC2s are regulated by neuromedin events, there may also be STAT-dependent transcriptional U (NMU) released from cholinergic neurons in the gut (62, events that underlie the chronicity of pain and itch. We an- 63) and somatosensory afferents in the lung (64). Vasoactive ticipate that investigating JAK signaling in neurons may unveil intestinal peptide (VIP) is another neuropeptide found to novel biochemistry with regard to JAK signaling and have activate lung ILC2s upon its release from cholinergic neurons http://www.jimmunol.org/ broad implications for the treatment of both chronic pain and of the vagal nodose ganglia, which, along with somatosensory itch disorders. neurons, also innervate the lung (65). Given that both NMU The significance of neuronal JAK1 signaling in itch is and VIP are expressed by somatosensory neurons, whether corroborated by clinical trials in which topical JAK inhibitors these neuropeptides also play an important role in regulating have demonstrated rapid anti-itch effects within 24–48 h of cutaneous inflammation is an exciting area of future inquiry initial treatment in AD patients prior to any detectable effect (64, 66, 67). One study suggests that VIP can alter the ca- on clinical skin inflammation (49, 50). Additionally, in a pacity of Langerhans cells to present Ags and thus inhibit the

small proof-of-concept study, we found that even in a chronic generation of Th1 cell responses (68). Finally, although the by guest on September 24, 2021 itch condition in which there is an absence of noticeable skin primary focus of research in the skin thus far has concentrated inflammation [chronic idiopathic pruritus or generalized on the role of neuropeptides, there is emerging interest in the pruritus of unknown origin (51)], patients experienced a rapid ability of small molecule neurotransmitters in mediating cu- reduction in itch symptoms in response to a JAK inhibitor taneous inflammation. (tofacitinib) (30). The importance of neuronal JAK1 in mediating itch is further reinforced by the finding that pa- Pathogen-neuron interactions tients with germline JAK1 gain-of-function mutations develop Recent studies have found that sensory neurons, like immune chronic pruritus that is selectively responsive to treatment with cells, are able to directly sense and respond to microbes. One a JAK inhibitor (ruxolitinib) over broader anti-inflammatory example is LPS, a major component of Gram-negative bacteria agents (i.e., systemic steroids) (52). Collectively, these stud- and a key endotoxin that binds TLR4. Along with being ies show that investigating cytokine-neuronal interactions immunostimulatory, LPS also directly activates sensory neurons can lead to novel therapeutic insights that can be exploited to modulate both pain and itch signaling. Although LPS in- for treatment of itch, pain, and possibly other sensory jection is known to induce pain but not itch (69), one study disorders. found that TLR4 signaling promotes histamine-mediated itch by potentiating TRPV1 activity (70). Although studies have Sensory neurons drive inflammatory skin disorders shown that sensory neurons detect LPS directly through TLR4 In contrast to other barrier surfaces, somatosensory neurons are (71–73), others have found that LPS can directly stimulate the primary source of neuropeptides in the skin. Historically sensory neurons in an TLR4-independent manner through associated with signaling in neural tissues, it is now recognized mechanical perturbation of the neuronal membrane, resulting that these small peptides can also act on other cell types, such as in the activation of TRPA1 (74, 75). Collectively, these studies keratinocytes and immune cells, provoking the hypothesis that demonstrate how bacterial endotoxins can directly manipulate sensory neurons directly and critically regulate skin inflam- the peripheral nervous system to modulate sensation. mation (53). This hypothesis is supported by a number of Pore-forming toxins (PFTs) are another class of virulence observational studies that document that patients with in- factors that, in contrast to classical endotoxins, are produced by flammatory skin disorders such as AD and psoriasis experi- Gram-positive bacteria, which commonly cause bacterial skin enced disease resolution in body parts that had a loss of infections such as cellulitis and necrotizing fasciitis. Notably, innervation (54–57). Similarly, in murine models of psoriasis, these infections are strongly associated with disproportionate + + surgical denervation, and chemical ablation of NaV1.8 TRPV1 levels of pain. Recent studies have shown that these PFTs can sensory nerve fibers also resulted in the improvement of disease penetrate and activate sensory neurons directly to evoke pain The Journal of Immunology 2833

suggest that specialized protective immune modules may also encode highly specific sensory and behavioral responses. In the setting of pain, the withdrawal reflex (acute pain) and/or aversion to movement (prolonged pain) may help to promote wound healing, prevent the spread of infection, and conserve host metabolic resources. In contrast to pain, the scratching reflex may help to promote the expulsion of macroparasites, toxins, and environmental irritants (80). Thus, scratching the skin in response to itch may parallel the “weep and sweep” responses promoted by type 2 inflammation in the intestine and airway. Finally, not only does the cytokine milieu dictate the sensation and behavioral response generated, sensory neurons, in turn, shape the immune response through the release of various neuropeptides. Collectively, advances in neuroimmunology demonstrate that the nervous system is an integral part of the overall immune response in both health and disease. FIGURE 2. Pathogens can directly activate sensory neurons to release neu- Three broad areas of investigation remain open to major ropeptides in skin immunity. b-glucan from C. albicans and PFTs released from advancement. First, the specific cellular sources of neuro- Downloaded from bacteria like S. aureus and S. pyogenes can activate sensory neurons. Stimulation modulatory cytokines during the course of an immune re- of these sensory neurons results in the release of neuropeptides such as CGRP, sponse and how these cells home toward and interact with which can directly influence cutaneous immunity by acting on immune cells. specific sensory neurons remains poorly defined. Second, which chronic inflammatory and sensory disorders can be (76, 77) (Fig. 2). Specifically, a-hemolysin, phenol-soluble modulated by targeting specific cytokines and/or neuropep- modulins, and the leukocidin g-hemolysin AB from Staphylococcus tides in human disease is an exciting area of therapeutic in- http://www.jimmunol.org/ aureus (76) and streptolysin S from Streptococcus pyogenes (77) quiry. Third, what specific mediators and signaling pathways were shown to critically mediate bacterial infection–associated pain drive the release of neuropeptides from neurons in the skin as in the skin through direct neuronal activation. Thus, it appears well as mucosal surfaces remains largely unknown. Ultimately, that, in addition to stimulating the host inflammatory re- additional insights into these processes will likely open new sponse, the bacterium can directly influence pain sensation avenues of therapeutic intervention for sensory, inflammatory, and behavior through a variety of toxins, likely independently and infectious disorders of the skin and beyond. of the generation of pain-associated cytokines such as IL-1b, a

IL-6, IL-17A, and TNF- . Future studies may reveal many by guest on September 24, 2021 more mechanisms by which bacteria and other microorgan- Acknowledgments isms are sensed by sensory neurons and if these signals can We thank members of the Kim Laboratory for reviewing the manuscript and Dr. Isaac Chiu for insightful discussions. modulate itch in addition to pain.

Sensory neurons mediate immunity Disclosures B.S.K. has served as a consultant for AbbVie, Inc., Menlo Therapeutics, and Similar to their contribution to inflammatory skin diseases, Pfizer, Inc., and on advisory boards for Cara Therapeutics, Incyte Corporation, neurons also play an important role in modulating protective Kiniksa Pharmaceuticals, Menlo Therapeutics, and Regeneron Pharmaceuti- immunity. Recent studies have demonstrated that intact pe- cals, Inc. B.S.K. is a stockholder of Locus Biosciences and is a founder and ripheral sensory innervation is critical for optimal production of chief scientific officer of Nuogen Pharma, Inc. The other authors have no IL-23 to drive antifungal immunity to Candida albicans.Ad- financial conflicts of interest. ministration of CGRP was sufficient to overcome the effects of denervation in this context (78). A study by Maruyama et al. References (79) suggests neurons detect C. albicans through the binding of 1. Pinho-Ribeiro, F. A., W. A. Verri, Jr., and I. M. Chiu. 2017. Nociceptor sensory neuronal dectin-1 to b-glucan, and this may stimulate the re- neuron-immune interactions in pain and inflammation. Trends Immunol. 38: 5–19. 2.Cook,A.D.,A.D.Christensen,D.Tewari,S.B.McMahon,andJ.A.Hamilton.2018. lease of CGRP (Fig. 2). Whether neurons can sense other fungi Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 39: 240–255. and modulate immunity in a similar fashion remains an in- 3. Azimi, E., J. Xia, and E. A. Lerner. 2016. Peripheral mechanisms of itch. Curr. Probl. Dermatol. 50: 18–23. triguing question. Similar to C. albicans, CGRP is also released 4. Ikoma, A., M. Steinhoff, S. Sta¨nder, G. Yosipovitch, and M. Schmelz. 2006. The by neurons upon S. pyogenes infection (Fig. 2). However, neurobiology of itch. Nat. Rev. Neurosci. 7: 535–547. 5. Meng, J., and M. Steinhoff. 2016. Molecular mechanisms of pruritus. Curr. Res. whereas CGRP appears to be protective in the setting of Transl. Med. 64: 203–206. C. albicans, it plays a detrimental role in S. pyogenes infection by 6. Ramsey, I. S., M. Delling, and D. E. Clapham. 2006. An introduction to TRP channels. Annu. Rev. Physiol. 68: 619–647. suppressing neutrophil recruitment and antibacterial immu- 7. de Lera Ruiz, M., and R. L. Kraus. 2015. Voltage-gated sodium channels: structure, nity (77). Ultimately, these studies bring forth a paradigm in function, pharmacology, and clinical indications. J. Med. Chem. 58: 7093–7118. which the sensory nervous system is both capable of sensing 8. Ringkamp, M., R. J. Schepers, S. G. Shimada, L. M. Johanek, T. V. Hartke, J. Borzan, B. Shim, R. H. LaMotte, and R. A. Meyer. 2011. A role for nociceptive, microbes directly and, in turn, shaping host immunity. myelinated nerve fibers in itch sensation. J. Neurosci. 31: 14841–14849. 9. Handwerker, H. O. 2014. Itch hypotheses: From pattern to specificity and to population coding. In Itch: Mechanisms and Treatment. E. Carstens and T. Akiyama, Conclusions eds. CRC Press, Boca Raton, FL, p. 1–9. The skin harbors a vast neuroimmune network that is poised 10. Sun, S., and X. Dong. 2016. Trp channels and itch. Semin. Immunopathol. 38: 293–307. to provide a rapid, coordinated response to a variety of envi- 11. Dong, X., and X. Dong. 2018. Peripheral and central mechanisms of itch. Neuron ronmental insults. Recent advances covered in this review 98: 482–494. 2834 BRIEF REVIEWS: THE SKIN NEUROIMMUNE AXIS

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