Journal of Shanghai Jiao Tong University (Medical Science) >
Research progress in neuroimmune disorders in atopic dermatitis
Received date: 2023-03-29
Accepted date: 2023-06-29
Online published: 2023-08-28
Supported by
National Natural Science Foundation of China(81874252)
Atopic dermatitis (AD) is a chronic inflammatory skin disease with the highest incidence in the world. The main clinical manifestations are eczema-like skin lesions, pruritus and xeroderma. Recent studies have revealed that sensory neurons in the skin lesions of AD patients can interact abnormally with keratinocytes (KC) and immune cells, leading to neuroimmune disorders. Among them, there are two types of sensory neurons involved in neuroimmune disorders, including histaminergic and non-histaminergic sensory neurons. In neuroimmune disorders, KC and immune cells activate sensory neurons to induce pruritus by secreting proinflammatory cytokines such as interleukin-4 (IL-4), IL-13, IL-31, IL-33, and thymic stromal lymphopoietin, as well as chemokines such as C-X-C motif chemokine ligand 12 (CXCL12) and CXCL10. In addition, neuropeptides such as nerve growth factor, brain-derived neurotrophic factor and artemin secreted by KC and immune cells can induce overgrowth of sensory neurons, thereby promoting neuroimmune disorders. At the same time, the excessive release of neuropeptides such as calcitonin gene-related peptide and substance P by sensory neurons can act on KC and immune cells, thereby aggravating skin inflammation. In recent years, many drugs targeting neuroimmune disorders are in preclinical studies, clinical trials and other stages, or have been marketed for the treatment of AD. Among them, our research group has found that lidocaine, a local anesthetic, can target neuroimmune disorders and relieve pruritus and skin inflammation in AD patients. At present, the role of neuroimmune disorders in AD has not been systematically discussed. Based on this, this article reviews the types of sensory neurons involved in neuroimmune disorders, the role of KC, immune cells and sensory neurons in neuroimmune disorders, as well as the therapeutic strategies targeting neuroimmune disorders.
Key words: atopic dermatitis (AD); neuroimmune; sensory neuron; immune cell; keratinocyte (KC)
Zhenquan XUAN , Xuanyi CHEN , Zhirong YAO . Research progress in neuroimmune disorders in atopic dermatitis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023 , 43(8) : 1049 -1055 . DOI: 10.3969/j.issn.1674-8115.2023.08.014
1 | GUO Y F, LI P, TANG J P, et al. Prevalence of atopic dermatitis in Chinese children aged 1-7 ys[J]. Sci Rep, 2016, 6: 29751. |
2 | LAUGHTER M R, MAYMONE M C, MASHAYEKHI S, et al. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990?2017[J]. Br J Dermatol, 2021, 184(2): 304-309. |
3 | FRAZIER W, BHARDWAJ N. Atopic dermatitis: diagnosis and treatment[J]. Am Fam Physician, 2020, 101(10): 590-598. |
4 | LANGAN S M, IRVINE A D, WEIDINGER S. Atopic dermatitis[J]. Lancet, 2020, 396(10247): 345-360. |
5 | TüZüN Y, ANTONOV M, DOLAR N, et al. Keratinocyte cytokine and chemokine receptors[J]. Dermatol Clin, 2007, 25(4): 467-476, vii. |
6 | KLEIN WOLTERINK R G J, WU G S, CHIU I M, et al. Neuroimmune interactions in peripheral organs[J]. Annu Rev Neurosci, 2022, 45: 339-360. |
7 | STEINHOFF M, AHMAD F, PANDEY A, et al. Neuroimmune communication regulating pruritus in atopic dermatitis[J]. J Allergy Clin Immunol, 2022, 149(6): 1875-1898. |
8 | CHURCH M K. Allergy, histamine and antihistamines[J]. Handb Exp Pharmacol, 2017, 241: 321-331. |
9 | BAUTISTA D M, WILSON S R, HOON M A. Why we scratch an itch: the molecules, cells and circuits of itch[J]. Nat Neurosci, 2014, 17(2): 175-182. |
10 | SCHAPER-GERHARDT K, ROSSBACH K, NIKOLOULI E, et al. The role of the histamine H4 receptor in atopic dermatitis and psoriasis[J]. Br J Pharmacol, 2020, 177(3): 490-502. |
11 | MURATA Y, SONG M, KIKUCHI H, et al. Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis[J]. J Dermatol, 2015, 42(2): 129-139. |
12 | YOSIPOVITCH G, ROSEN J D, HASHIMOTO T. Itch: from mechanism to (novel) therapeutic approaches[J]. J Allergy Clin Immunol, 2018, 142(5): 1375-1390. |
13 | CHAN L S, ROBINSON N, XU L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis[J]. J Invest Dermatol, 2001, 117(4): 977-983. |
14 | ZHENG T, OH M H, OH S Y, et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling[J]. J Invest Dermatol, 2009, 129(3): 742-751. |
15 | OETJEN L K, MACK M R, FENG J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch[J]. Cell, 2017, 171(1): 217-228. e13. |
16 | SINGER E M, SHIN D B, NATTKEMPER L A, et al. IL-31 is produced by the malignant T-cell population in cutaneous T-Cell lymphoma and correlates with CTCL pruritus[J]. J Invest Dermatol, 2013, 133(12): 2783-2785. |
17 | SONKOLY E, MULLER A, LAUERMA A I, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation[J]. J Allergy Clin Immunol, 2006, 117(2): 411-417. |
18 | TEY H L, CAO T, NATTKEMPER L A, et al. Pathophysiology of pruritus in primary localized cutaneous amyloidosis[J]. Br J Dermatol, 2016, 174(6): 1345-1350. |
19 | CEVIKBAS F, WANG X, AKIYAMA T, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1[J]. J Allergy Clin Immunol, 2014, 133(2): 448-460. |
20 | BECK L A, CORK M J, AMAGAI M, et al. Type 2 inflammation contributes to skin barrier dysfunction in atopic dermatitis[J]. JID Innov, 2022, 2(5): 100131. |
21 | SOUMELIS V, RECHE P A, KANZLER H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP[J]. Nat Immunol, 2002, 3(7): 673-680. |
22 | WILSON S R, THé L, BATIA L M, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch[J]. Cell, 2013, 155(2): 285-295. |
23 | LEE W J, SHIM W S. Cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus[J]. Front Immunol, 2021, 12: 772941. |
24 | OYOSHI M K, LARSON R P, ZIEGLER S F, et al. Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression[J]. J Allergy Clin Immunol, 2010, 126(5): 976-984, 984. e1-5. |
25 | CHAN B C L, LAM C W K, TAM L S, et al. IL33: roles in allergic inflammation and therapeutic perspectives[J]. Front Immunol, 2019, 10: 364. |
26 | HUANG J T, GANDINI M A, CHEN L N, et al. Hyperactivity of innate immunity triggers pain via TLR2-IL-33-mediated neuroimmune crosstalk[J]. Cell Rep, 2020, 33(1): 108233. |
27 | LIU B Y, TAI Y, ACHANTA S, et al. IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy[J]. Proc Natl Acad Sci USA, 2016, 113(47): E7572-E7579. |
28 | TRIER A M, MACK M R, FREDMAN A, et al. IL-33 signaling in sensory neurons promotes dry skin itch[J]. J Allergy Clin Immunol, 2022, 149(4): 1473-1480. e6. |
29 | NAKAMURA N, TAMAGAWA-MINEOKA R, YASUIKE R, et al. Stratum corneum interleukin-33 expressions correlate with the degree of lichenification and pruritus in atopic dermatitis lesions[J]. Clin Immunol, 2019, 201: 1-3. |
30 | ROGGENKAMP D, FALKNER S, ST?B F, et al. Atopic keratinocytes induce increased neurite outgrowth in a coculture model of porcine dorsal root ganglia neurons and human skin cells[J]. J Invest Dermatol, 2012, 132(7): 1892-1900. |
31 | SOLINSKI H J, RUKWIED R, SCHMELZ M. Microinjection of pruritogens in NGF-sensitized human skin[J]. Sci Rep, 2021, 11(1): 21490. |
32 | TAKANO N, SAKURAI T, OHASHI Y, et al. Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model[J]. Br J Dermatol, 2007, 156(2): 241-246. |
33 | KOWIA?SKI P, LIETZAU G, CZUBA E, et al. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity[J]. Cell Mol Neurobiol, 2018, 38(3): 579-593. |
34 | F?LSTER-HOLST R, PAPAKONSTANTINOU E, RüDRICH U, et al. Childhood atopic dermatitis-brain-derived neurotrophic factor correlates with serum eosinophil cationic protein and disease severity[J]. Allergy, 2016, 71(7): 1062-1065. |
35 | GUSEVA D, RüDRICH U, KOTNIK N, et al. Neuronal branching of sensory neurons is associated with BDNF-positive eosinophils in atopic dermatitis[J]. Clin Exp Allergy, 2020, 50(5): 577-584. |
36 | MUROTA H, IZUMI M, ABD EL-LATIF M I, et al. Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis[J]. J Allergy Clin Immunol, 2012, 130(3): 671-682. e4. |
37 | HIDAKA T, OGAWA E, KOBAYASHI E H, et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin[J]. Nat Immunol, 2017, 18(1): 64-73. |
38 | J?RVIKALLIO A, HARVIMA I T, NAUKKARINEN A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema[J]. Arch Dermatol Res, 2003, 295(1): 2-7. |
39 | SALOMON J, BARAN E. The role of selected neuropeptides in pathogenesis of atopic dermatitis[J]. J Eur Acad Dermatol Venereol, 2008, 22(2): 223-228. |
40 | KUBANOV A A, KATUNINA O R, CHIKIN V V. Expression of neuropeptides, neurotrophins, and neurotransmitters in the skin of patients with atopic dermatitis and psoriasis[J]. Bull Exp Biol Med, 2015, 159(3): 318-322. |
41 | HAN S B, KIM H, CHO S H, et al. Protective effect of botulinum toxin type A against atopic dermatitis-like skin lesions in NC/Nga mice[J]. Dermatol Surg, 2017, 43(Suppl 3): S312-S321. |
42 | YIN Q Q, SUN L B, CAI X J, et al. Lidocaine ameliorates psoriasis by obstructing pathogenic CGRP signaling-mediated sensory neuron-dendritic cell communication[J]. J Invest Dermatol, 2022, 142(8): 2173-2183. e6. |
43 | ROGGENKAMP D, K?PNICK S, ST?B F, et al. Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model[J]. J Invest Dermatol, 2013, 133(6): 1620-1628. |
44 | SHI X, WANG L, CLARK J D, et al. Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways[J]. Regul Pept, 2013, 186: 92-103. |
45 | ANTúNEZ C, TORRES M J, LóPEZ S, et al. Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigen-positive T cells in patients with atopic dermatitis[J]. Br J Dermatol, 2009, 161(3): 547-553. |
46 | SUN P Y, LI H G, XU Q Y, et al. Lidocaine alleviates inflammation and pruritus in atopic dermatitis by blocking different population of sensory neurons[J]. Br J Pharmacol, 2023, 180(10): 1339-1361. |
47 | LIU J Y, HU J H, ZHU Q G, et al. Effect of matrine on the expression of substance P receptor and inflammatory cytokines production in human skin keratinocytes and fibroblasts[J]. Int Immunopharmacol, 2007, 7(6): 816-823. |
48 | RAAP M, RüDRICH U, ST?NDER S, et al. Substance P activates human eosinophils[J]. Exp Dermatol, 2015, 24(7): 557-559. |
49 | FRIEDMAN S, LEVI-SCHAFFER F. Substance P and eosinophils: an itchy connection[J]. Exp Dermatol, 2015, 24(12): 918-919. |
50 | PAVLOVIC S, DANILTCHENKO M, TOBIN D J, et al. Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice[J]. J Invest Dermatol, 2008, 128(2): 434-446. |
51 | SERHAN N, BASSO L, SIBILANO R, et al. House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation[J]. Nat Immunol, 2019, 20(11): 1435-1443. |
52 | WHEELER J J, LASCELLES B D, OLIVRY T, et al. Itch-associated neuropeptides and their receptor expression in dog dorsal root ganglia and spinal cord[J]. Acta Derm Venereol, 2019, 99(12): 1131-1135. |
53 | MENG J, MORIYAMA M, FELD M, et al. New mechanism underlying IL-31-induced atopic dermatitis[J]. J Allergy Clin Immunol, 2018, 141(5): 1677-1689. e8. |
54 | GOODERHAM M J, HONG H C, ESHTIAGHI P, et al. Dupilumab: a review of its use in the treatment of atopic dermatitis[J]. J Am Acad Dermatol, 2018, 78(3 Suppl 1): S28-S36. |
55 | NEZAMOLOLAMA N, FIELDHOUSE K, METZGER K, et al. Emerging systemic JAK inhibitors in the treatment of atopic dermatitis: a review of abrocitinib, baricitinib, and upadacitinib[J]. Drugs Context, 2020, 9: 2020-8-5. |
56 | WOLLENBERG A, WEIDINGER S, WORM M, et al. Tralokinumab in atopic dermatitis[J]. J Dtsch Dermatol Ges, 2021, 19(10): 1435-1442. |
57 | RUZICKA T, HANIFIN J M, FURUE M, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis[J]. N Engl J Med, 2017, 376(9): 826-835. |
58 | KABASHIMA K, MATSUMURA T, KOMAZAKI H, et al. Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate-to-severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: results from two phase Ⅲ, long-term studies[J]. Br J Dermatol, 2022, 186(4): 642-651. |
59 | SILVERBERG J I, PINTER A, PULKA G, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus[J]. J Allergy Clin Immunol, 2020, 145(1): 173-182. |
60 | WELSH S E, XIAO C, KADEN A R, et al. Neurokinin-1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial[J]. J Eur Acad Dermatol Venereol, 2021, 35(5): e338-e340. |
61 | LEE Y W, WON C H, JUNG K, et al. Efficacy and safety of PAC-14028 cream - a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase Ⅱb randomized trial[J]. Br J Dermatol, 2019, 180(5): 1030-1038. |
62 | RATCHATASWAN T, BANZON T M, THYSSEN J P, et al. Biologics for treatment of atopic dermatitis: current status and future prospect[J]. J Allergy Clin Immunol Pract, 2021, 9(3): 1053-1065. |
63 | PENG G, MU Z Z, CUI L X, et al. Anti-IL-33 antibody has a therapeutic effect in an atopic dermatitis murine model induced by 2, 4-dinitrochlorobenzene[J]. Inflammation, 2018, 41(1): 154-163. |
64 | ZENG D, CHEN C, ZHOU W, et al. TRPA1 deficiency alleviates inflammation of atopic dermatitis by reducing macrophage infiltration[J]. Life Sci, 2021, 266: 118906. |
65 | LI H, LI C, ZHANG H, et al. Effects of lidocaine on regulatory T cells in atopic dermatitis[J]. J Allergy Clin Immunol, 2016, 137(2): 613-617. e5. |
66 | JIAO Q Q, WANG H L, HU Z L, et al. Lidocaine inhibits staphylococcal enterotoxin-stimulated activation of peripheral blood mononuclear cells from patients with atopic dermatitis[J]. Arch Dermatol Res, 2013, 305(7): 629-636. |
67 | DRUCKER A M, WANG A R, LI W Q, et al. The burden of atopic dermatitis: summary of a report for the National Eczema Association[J]. J Invest Dermatol, 2017, 137(1): 26-30. |
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