Neuroimmune communication regulating pruritus in atopic dermatitis

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus. Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus. Atopic dermatitis (AD) is a very common chronic inflammatory skin disease worldwide.1Williams H. Robertson C. Stewart A. Aït-Khaled N. Anabwani G. Anderson R. et al.Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood.J Allergy Clin Immunol. 1999; 103: 125-138Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar It affects children and adults and occurs with different severities and phenotypes.2Langan S.M. Irvine A.D. Weidinger S. Atopic dermatitis.Lancet. 2020; 396: 345-360Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar,3Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Prim. 2018; 4: 1Crossref PubMed Scopus (186) Google Scholar A century ago, AD was also defined as “neurodermatitis,” suggesting a close connection between the nervous system and the immune system.4Brocq L. L’eczéma considéré comme une eaction cutaneé.Ann Dermatol Syph. 1903; 4: 172Google Scholar,5Jaquet L. La pratique dermatologique.traité de dermatologie appliquée. 1904; 5: 341Google Scholar Recent molecular, cellular, and patient-based studies have unfolded a close relationship between the sensory and autonomic nervous system as well as the adaptive/innate immune system in the pathophysiology in AD.6Yosipovitch G. Berger T. Fassett M.S. Neuroimmune interactions in chronic itch of atopic dermatitis.J Eur Acad Dermatol Venereol. 2020; 34: 239-250Crossref PubMed Scopus (0) Google Scholar, 7Oetjen L.K. Kim B.S. Interactions of the immune and sensory nervous systems in atopy.FEBS J. 2018; 285: 3138-3151Crossref PubMed Scopus (16) Google Scholar, 8Tran B.W. Papoiu A.D.P. Russoniello C.V. Wang H. Patel T.S. Chan Y.-H. et al.Effect of itch, scratching and mental stress on autonomic nervous system function in atopic dermatitis.Acta Derm Venereol. 2010; 90: 354-361Crossref PubMed Scopus (0) Google Scholar, 9Mack M.R. Kim B.S. The itch-scratch cycle: a neuroimmune perspective.Trends Immunol. 2018; 39: 980-991Abstract Full Text Full Text PDF PubMed Google Scholar, 10Cevikbas F. Steinhoff A. Homey B. Steinhoff M. Neuroimmune interactions in allergic skin diseases.Curr Opin Allergy Clin Immunol. 2007; 7: 365-373Crossref PubMed Scopus (47) Google Scholar The commonality between all phenotypes, acuities, and severities in AD is that they all are pruritic, and characterized by a vicious “itch-scratch cycle,” indicating a critical role of sensory nerves in AD. Dependent on the trigger, AD can start at different pathophysiological pillars, resulting in the same clinical end point, AD (Fig 1).11Steinhoff M. Ständer S. Seeliger S. Ansel J.C. Schmelz M. Luger T. Modern aspects of cutaneous neurogenic inflammation.Arch Dermatol. 2003; 139: 1479-1488Crossref PubMed Scopus (283) Google Scholar For example, endogenous or exogenous trigger factors of AD such as protons, microbes, irritants, or allergens can both directly or indirectly, via epidermal and immune cells, activate high-affinity receptors (eg, transient receptor potential [TRP] cation channels, Toll-like receptors [TLRs], and protease-activated receptors [PARs]) on peripheral sensory nerve endings (Figs 2 and 3).12Baral P. Mills K. Pinho-Ribeiro F.A. Chiu I.M. Pain and itch: beneficial or harmful to antimicrobial defense?.Cell Host Microbe. 2016; 19: 755-759Abstract Full Text Full Text PDF PubMed Google Scholar,13Buddenkotte J. Steinhoff M. Pathophysiology and therapy of pruritus in allergic and atopic diseases.Allergy. 2010; 65: 805-821Crossref PubMed Scopus (98) Google Scholar Activation of sensory nerve endings leads to depolarization and electric transduction, which in turn leads to the release of further neuromediators from central primary afferent nerve endings into the dorsal horn of spinal cord (Fig 4).14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. Clinical presentation, management, and pathophysiology of neuropathic itch.Lancet Neurol. 2018; 17: 709-720Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,15Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Google Scholar Notably, itch and pain do not completely share the same anatomical structures or molecular receptor pathways.14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. Clinical presentation, management, and pathophysiology of neuropathic itch.Lancet Neurol. 2018; 17: 709-720Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In the brain, different anatomical centers become activated, resulting in scratching or withdrawal reflex.16Schmelz M. Itch processing in the skin.Front Med. 2019; 6: 167Crossref Scopus (12) Google Scholar, 17Mochizuki H. Schut C. Nattkemper L.A. Yosipovitch G. Brain mechanism of itch in atopic dermatitis and its possible alteration through non-invasive treatments.Allergol Int. 2017; 66: 14-21Abstract Full Text Full Text PDF PubMed Google Scholar, 18Ikoma A. Steinhoff M. Ständer S. Yosipovitch G. Schmelz M. The neurobiology of itch.Nat Rev Neurosci. 2006; 7: 535-547Crossref PubMed Scopus (703) Google Scholar, 19Ständer S. Schmelz M. Chronic itch and pain--similarities and differences.Eur J Pain. 2006; 10: 473-478Crossref PubMed Scopus (0) Google Scholar Thus, neuroimmune circuits implying different neuromediators play a significant role in regulating innate and adaptive immunity, skin barrier dysfunction, and pruritus in AD.6Yosipovitch G. Berger T. Fassett M.S. Neuroimmune interactions in chronic itch of atopic dermatitis.J Eur Acad Dermatol Venereol. 2020; 34: 239-250Crossref PubMed Scopus (0) Google ScholarFig 2Connection of neuroinflammation and itch or pain in AD. Exogenous or endogenous trigger factors of AD activate various high-affinity receptors on sensory nerve endings (C-fibers) in the epidermis or dermis. “Electric firing” is transduced via spinal cord and contralateral spinothalamic tract to specific brain centers to induce the itch perception, resulting in scratching response. Itch mediators comprise different molecular family members such as amines (eg, histamine and serotonin), proteases, cytokines (eg, IL-31, IL-4, and IL-13), neuromediators (eg, ET-1), chemokines, eicosanoids (eg, LTC4 and PGE2), protons, toxins, allergens, and more (see Table I). In an “axon reflex” mechanism, the stimulus stimulates neighboring nerve endings to release neuromediators (eg, SP, CGRP, BNP, PACAP, and ET-1) to the skin, thereby aggravating inflammation through immunomodulation of adaptive and innate immune cells. Neuromediators also contribute to vasodilation (erythema) and plasma extravasation (edema), leading to the recruitment of more leukocytes to the site of inflammation. Cytokines and neuromediators impair skin barrier function, perpetuating inflammation and itch. Baso, Basophil; Eos, eosinophil; ET-1, endothelin-1; H+, proton; HDM, house dust mite; IL, interleukin; KC, keratinocyte; LC, Langerhans cell; LN, lymph node; LTC4, leukotriene C4; Macro, macrophage; MC, mast cell; PACAP, pituitary adenylate cyclase–activating peptide; PAR2, protease-activated receptor-2; PGE2, prostaglandin E2; SP, substance P.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Targets to treat peripheral and central pruritus. Targets for treatment of chronic or recalcitrant itch are blockers of peripheral mediators or receptors on nerve endings. They belong to various family members (right box). Until now, it is unknown which pathways are critical in addition to interleukin receptors, or as topicals. Intracellular signal transduction pathway mediators (bottom box) modulate neuromediator release and modify transcription of genes for mediators and receptors in DRG neurons. Selective neuron populations signal either itch (called NP1, NP2, NP3) and/or pain to the central primary afferent projection neurons (red) in the dorsal horn of spinal cord. Various mediators can be released into the spinal cord, activating receptors in Lamina I and II of the dorsal horn. Projection neurons (left box) transmit the signal to the brain (see also Fig 2). Itch signaling is under control of excitatory (aggravating, green) or inhibitory interneurons and mediators (suppression, red). Mechanically induced itch uses, in mice, other transmitters (eg, NPY, purple) than chemically induced itch (green). Blockage of stimulating mediators or their corresponding receptors, or enhancement. DYN, Dynorphin; ERK1/2, extracellular signal-regulated kinase 1/2; HDM, house dust mite; GABA, gamma-aminobutyric acid; GAL, galanin; GLY, glycine; GRP, gastrin-releasing peptide; GRPR, GRP receptor; LT, leukotriene; NK1R, neurokinin type 1 receptor; NP, neuronal pentraxin; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase–activating peptide; PAR2, protease-activated receptor-2; PGE2, prostaglandin E2; SP, substance P; TR4, testicular nuclear receptor 4; TrkA, topomyosin receptor kinase A.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Neuronal cytokine receptors mediate itch, neuroinflammation, and nerve sprouting in AD. TH2 and type 2 innate lymphoid cells release cytokines such as IL-4, IL-13, and IL-31, which activate high-affinity receptors (eg, IL-4Rα, IL-13Rα1, and IL31RA) on sensory nerve endings in skin. Receptor activation induces (a) induction of itch in the CNS, (b) nerve sprouting and thus sensitization of skin via pSTAT3 signaling, (c) activation of ERK1/2 and JAK/STAT to modulate mRNA and protein expression levels, thereby changing mediator and receptor levels on nerves; and (d) receptor-mediated Ca2+ activation (with or without TRP ion channel activation), which stimulates SNARE-protein–mediated release of neuropeptides (eg, SP, BNP, and CGRP) to induce neuroinflammation. Neuromediators modulate function of adaptive and innate immune cells to produce more cytokines that lower skin barrier function and produce more cytokine-mediated inflammation. Thus, neuroimmune circuits are critically involved in the triangle of immune dysregulation, skin barrier dysfunction, and neuroinflammation/itch. CNS, Central nervous system; DC, dendritic cell; ERK1/2, extracellular signal-regulated kinase 1/2; IL-13Rα1, IL-13 receptor-alpha 1; IL-13RA, IL-13 receptor A; ILC2, type 2 innate lymphoid cell; KC, keratinocyte; MC, mast cell; NSF, N-ethylmaleimide-sensitive factor; SNARE, soluble NSF attachment protein receptor; SP, substance P.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Here, we highlight our recent knowledge how neuroimmune circuits and their mediators/pathways control neuroinflammation and pruritus in AD, and elucidate how this knowledge can translate into new therapeutic strategies for AD. For decades, dermatologists have been discussing to which extent AD20Mendelsohm H.V. Atopic eczema (allergic eczema).Arch Derm Syphilol. 1946; 53: 656-658PubMed Google Scholar, 21Elias P.M. Steinhoff M. “Outside-to-inside” (and now back to “outside”) pathogenic mechanisms in atopic dermatitis.J Invest Dermatol. 2008; 128: 1067-1070Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 22Bieber T. Atopic dermatitis.N Engl J Med. 2008; 358: 1483-1494Crossref PubMed Scopus (1484) Google Scholar, 23Czarnowicki T. He H. Krueger J.G. Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics.J Allergy Clin Immunol. 2019; 143: 1-11Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar is a neurodermatitis,4Brocq L. L’eczéma considéré comme une eaction cutaneé.Ann Dermatol Syph. 1903; 4: 172Google Scholar,24Borelli S. Gehrken H. [Potassium dichromate test reaction in atopic neurodermitis].Hautarzt. 1971; 22: 450PubMed Google Scholar, 25Ackermann A. Neurodermatitis.Dermatologica. 1949; 98: 370PubMed Google Scholar, 26Wüthrich B. Storck H. Grob P. Schwarz-Speck M. Immunopathology of neurodermatitis.Arch Dermatol Forsch. 1972; 244: 327-332Crossref PubMed Scopus (6) Google Scholar, 27Neurodermatitis Fölster-Holst R. atopy of the skin [in German].Ophthalmologe. 2017; 114: 498-503PubMed Google Scholar or vice versa. Important molecular and translational findings indicate that in most cases AD is a “flare that itches” and not an “itch that flares,” with the exception likely in habitual scratching or stress-induced itch. Immunohistochemistry validated that clinically unremarkable (“nonlesional”) skin already consists of inflammatory cells that produce neuroimmune mediators, suggesting that in pruritic skin microinflammation is already imminent.28Renert-Yuval Y. Del Duca E. Pavel A.B. Fang M. Lefferdink R. Wu J. et al.The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults.J Allergy Clin Immunol. 2021; 148: 148-163Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,29He H. Del Duca E. Diaz A. Kim H.J. Gay-Mimbrera J. Zhang N. et al.Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities.J Allergy Clin Immunol. 2021; 147: 1369-1380Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Even in prurigo form of AD, microinflammation and mediators can be detected.30Tsoi LC, Hacini-Rachinel F, Fogel P, Rousseau F, Xing X, Patrick MT, et al. Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab [published online ahead of print November 9, 2021]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2021.10.004.Google Scholar, 31Weigelt N. Metze D. Ständer S. Prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients.J Cutan Pathol. 2010; 37: 578-586Crossref PubMed Scopus (70) Google Scholar, 32Belzberg M. Alphonse M.P. Brown I. Williams K.A. Khanna R. Ho B. et al.Prurigo nodularis is characterized by systemic and cutaneous T helper 22 immune polarization.J Invest Dermatol. 2021; 141: 2208-2218.e14Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Thus, independent as to whether endogenous/exogenous trigger factors may first activate keratinocytes, nerves, or immune cells, it culminates in the same clinical end point, eczema (Fig 1). For example, TH2-mediated inflammation releases cytokines (eg, IL-4, IL-13, and IL-31) that generate/aggravate skin barrier dysfunction, induce pruritus (eg, substance P and endothelin-1 [ET-1]), and stimulate more inflammatory mediators perpetuating TH2- (later also TH1)-inflammation (Fig 1). In addition, environmental triggers (eg, house dust mite and irritant) in liaison with impaired skin barrier result in inflammation (eg, thymic stromal lymphopoietin [TSLP]), leading to itch (eg, TSLP and proteases), resulting in scratching (Fig 1).3Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Prim. 2018; 4: 1Crossref PubMed Scopus (186) Google Scholar,33Steinhoff M. Cevikbas F. Yeh I. Chong K. Buddenkotte J. Ikoma A. Evaluation and management of a patient with chronic pruritus.J Allergy Clin Immunol. 2012; 130: 1015-1016.e7Abstract Full Text Full Text PDF PubMed Google Scholar,34Weidinger S. Novak N. Atopic dermatitis.Lancet. 2016; 387: 1109-1122Abstract Full Text Full Text PDF PubMed Scopus (1005) Google Scholar Accordingly, genetic predisposition to skin barrier dysfunction (eg, filaggrin mutation) results in dry skin, more scratching, and induction of inflammation, which subsequently increases itch and scratching.3Weidinger S. Beck L.A. Bieber T. Kabashima K. Irvine A.D. Atopic dermatitis.Nat Rev Dis Prim. 2018; 4: 1Crossref PubMed Scopus (186) Google Scholar,35Szöllősi A.G. McDonald I. Szabó I.L. Meng J. van den Bogaard E. Steinhoff M. TLR3 in chronic human itch: a keratinocyte-associated mechanism of peripheral itch sensitization.J Invest Dermatol. 2019; 139: 2393-2396.e6Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Likewise, without exogenous triggers, endogenous mediators (eg, pH changes, lipids, and “stress peptides”) may induce inflammation and itch by activating receptors on both immune cells and nerves (eg, TRP vanilloid [TRPV] 1), sphingosine receptor, substance P, and brain natriuretic peptide [BNP]), resulting in more scratching and subsequently enhanced skin barrier dysfunction,36Kido-Nakahara M. Buddenkotte J. Kempkes C. Ikoma A. Cevikbas F. Akiyama T. et al.Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus.J Clin Invest. 2014; 124: 2683-2695Crossref PubMed Scopus (60) Google Scholar, 37Meng J. Moriyama M. Feld M. Buddenkotte J. Buhl T. Szöllösi A. et al.New mechanism underlying IL-31-induced atopic dermatitis.J Allergy Clin Immunol. 2018; 141: 1677-1689.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 38Park CW, Kim BJ, Lee YW, Won C, Park CO, Chung BY, et al. Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: phase 3, randomized, vehicle-controlled study (CAPTAIN-AD) [published online ahead of print October 2, 2021]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2021.09.024.Google Scholar a fact that cannot be explained by exogenous triggers alone. Finally, stress-related habitual scratching of patients with AD results in skin barrier disruption, inflammation, and itch, as we observe in AD-associated prurigo, lichen simplex, or stress-related habitual scratching.37Meng J. Moriyama M. Feld M. Buddenkotte J. Buhl T. Szöllösi A. et al.New mechanism underlying IL-31-induced atopic dermatitis.J Allergy Clin Immunol. 2018; 141: 1677-1689.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,39Ständer S. Steinhoff M. Schmelz M. Weisshaar E. Metze D. Luger T. Neurophysiology of pruritus: cutaneous elicitation of itch.Arch Dermatol. 2003; 139: 1463-1470Crossref PubMed Scopus (174) Google Scholar Another often overseen caveat in AD is that gene mutations that have been attributed to contribute to the pathophysiology in AD also directly compromise neuronal function (eg, neuronal IL-4Rα, IL-13Rα1, IL-13Rα2, TSLP receptor, histamine H4 receptor, IL-31, TSLP, and IL-4), encoding for mediators/receptors directly modulating neuronal function (reviewed by Bin and Leung40Bin L. Leung D.Y.M. Genetic and epigenetic studies of atopic dermatitis.Allergy Asthma Clin Immunol. 2016; 12: 52Crossref PubMed Scopus (144) Google Scholar), or generating an environment with higher concentrations for itch mediators (eg, through filaggrin-, serine peptidase inhibitor Kazal type 5–induced skin barrier dysfunction). Thus, gain-of-function mutations in these receptor genes or mediator genes do not only contribute to dysregulation of immunity and skin barrier function but also enhance neuronal sensitization and thus pruritus.14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. Clinical presentation, management, and pathophysiology of neuropathic itch.Lancet Neurol. 2018; 17: 709-720Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,18Ikoma A. Steinhoff M. Ständer S. Yosipovitch G. Schmelz M. The neurobiology of itch.Nat Rev Neurosci. 2006; 7: 535-547Crossref PubMed Scopus (703) Google Scholar,41Steinhoff M. Bienenstock J. Schmelz M. Maurer M. Wei E. Bíró T. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus.J Invest Dermatol. 2006; 126: 1705-1718Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar Moreover, an impaired skin barrier facilitates increased penetration of pruritic substances (eg, proteases, irritants, allergens, and toxins) to epidermal nerves, allowing activation of the PAR2/TSLP or TLR3/TSLP/endothelin-1 axis, stimulating itch and neuroinflammation in AD.35Szöllősi A.G. McDonald I. Szabó I.L. Meng J. van den Bogaard E. Steinhoff M. TLR3 in chronic human itch: a keratinocyte-associated mechanism of peripheral itch sensitization.J Invest Dermatol. 2019; 139: 2393-2396.e6Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar,42Steinhoff M. Vergnolle N. Young S.H. Tognetto M. Amadesi S. Ennes H.S. et al.Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.Nat Med. 2000; 6: 151-158Crossref PubMed Scopus (777) Google Scholar, 43Steinhoff M. Neisius U. Ikoma A. Fartasch M. Heyer G. Skov P.S. et al.Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.J Neurosci. 2003; 23: 6176-6180Crossref PubMed Google Scholar, 44Wilson S.R. Thé L. Batia L.M. Beattie K. Katibah G.E. McClain S.P. et al.The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell. 2013; 155: 285-295Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar Notably, histamine concentrations are not increased in patients with AD, in contrast to tryptase, explaining why histamine-1 receptor antagonists are not particularly effective in AD when nonsedative.43Steinhoff M. Neisius U. Ikoma A. Fartasch M. Heyer G. Skov P.S. et al.Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.J Neurosci. 2003; 23: 6176-6180Crossref PubMed Google Scholar,45Schmelz M. How do neurons signal itch?.Front Med. 2021; 8643006Crossref Scopus (3) Google Scholar Together, these findings explain why patients with or without acute exogenous trigger factor, patients without skin barrier gene mutation, but with habitual scratching, stress, with gene mutations for immune dysregulation all develop the same clinical end point, AD, because all parts of the circuit lead to, or are already based on, dysregulated type 2 inflammation (Figs 1 and 2). This dysregulation also implies higher expression levels of pruritic cytokine receptors (whether genetically or functionally) on nerves, resulting in enhanced release of neuromediators into the epidermis and dermis, thereby aggravating inflammation through stimulating innate and adaptive immune cells. In addition, skin barrier dysfunction (through enhanced levels of barrier-disrupting cytokines, release of pruritic mediators) induces release of more itch mediators, which we suggest to define as the peripheral sensitization loop in AD (Fig 2).11Steinhoff M. Ständer S. Seeliger S. Ansel J.C. Schmelz M. Luger T. Modern aspects of cutaneous neurogenic inflammation.Arch Dermatol. 2003; 139: 1479-1488Crossref PubMed Scopus (283) Google Scholar After sensory nerve (C-fiber) depolarization/activation, the stimulus is transduced to the brain via the contralateral spinothalamic tract, resulting in scratch response in AD.14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. Clinical presentation, management, and pathophysiology of neuropathic itch.Lancet Neurol. 2018; 17: 709-720Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The novel central itch mechanisms have been described in detail elsewhere.45Schmelz M. How do neurons signal itch?.Front Med. 2021; 8643006Crossref Scopus (3) Google Scholar, 46Lay M. Dong X. Neural mechanisms of itch.Annu Rev Neurosci. 2020; 43: 187-205Crossref PubMed Scopus (20) Google Scholar, 47Chen Z.-F. A neuropeptide code for itch.Nat Rev Neurosci. 2021; 22: 758-776Crossref PubMed Scopus (4) Google Scholar For understanding central itch circuits in AD, one can anticipate that in addition to the peripheral sensitization mechanisms of itch in AD, dysregulations of central circuits play a role in a chronic-relapsing disease such as AD and AD-associated prurigo. On a molecular level, sensory C-fibers can be distinguished into peptidergic and nonpeptidergic (NP) C-fibers.48Roosterman D. Goerge T. Schneider S.W. Bunnett N.W. Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.Physiol Rev. 2006; 86: 1309-1379Crossref PubMed Scopus (412) Google Scholar,49Cevikbas F. Lerner E.A. Physiology and pathophysiology of itch.Physiol Rev. 2020; 100: 945-982Crossref PubMed Scopus (31) Google Scholar Peptidergic C-fibers release neuropeptides such as Substance P (SP), for example, and contribute to itch and neuroinflammation.11Steinhoff M. Ständer S. Seeliger S. Ansel J.C. Schmelz M. Luger T. Modern aspects of cutaneous neurogenic inflammation.Arch Dermatol. 2003; 139: 1479-1488Crossref PubMed Scopus (283) Google Scholar Based on RNA-sequencing data in mice, 4 NP fibers (NP1-4) exist. The current concept (based on mouse data) is that NP1 is involved in neuropathic pain and itch, whereas NP2 and NP3 are predominantly implicated in itch sensation. Because NP3 fibers harbor IL-31+ neurons and release BNP, it is suggested that higher activation of NP3 fibers (eg, by IL-31) is involved in transduction of inflammatory itch in AD, mediated to the spinal cord via BNP.14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. Clinical presentation, management, and pathophysiology of neuropathic itch.Lancet Neurol. 2018; 17: 709-720Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,50Mishra S.K. Hoon M.A. The cells and circuitry for itch responses in mice.Science. 2013; 340: 968-971Crossref PubMed Scopus (306) Google Scholar Less is known in that respect for IL-4, IL-13, and TSLP. On the basis of these molecular neuroscientific findings, one may speculate that there is a neuronal separation in AD where neuron-activating cytokines may use different molecular NP pathways to induce itch in AD (Fig 3). Thus, irritation- or scratching-induced TSLP released from keratinocytes may use different neuromediators in dorsal root ganglion (DRG) or spinal cord than IL-31, for example. Whether this is the case needs to be clarified. This may be of importance if in chronic neuropathic diseases one wants to block selective pathways, and not all. Dysregulated neuronal circuits in the spinal cord also play a role in the chronification of itch behavior, for example, by lowering the threshold, thereby inducing easier an itch stimulus, which may contribute to the clinical observation in patients with AD of uncontrolled scratching behavior toward minimal stimuli such as touch or wind blow. Along that line, frequently stimulated projection neurons (where BNP activates release of gastrin-releasing peptide, for example), together with an impaired control by “inhibitory” interneurons (which use, eg, somatostatin [SST] and dynorphin), contribute to central sensitization of itch, at least in rodents.14Steinhoff M. Schmelz M. Szabó I.L. Oaklander A.L. C