Staphylococcus aureus: The Bug Behind the Itch in Atopic Dermatitis

Journal of Investigative Dermatology, Journal Year: 2024, Volume and Issue: 144(5), P. 950 - 953

Published: Feb. 29, 2024

Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins are complex, and it considered both defense mechanism cause disease that leads to inflammation psychological stress. Considerable progress has been made in understanding the processes trigger itch, particularly pruritoceptive generated skin. This perspective review discusses implications recent observation V8 protease expressed by Staphylococcus aureus can directly sensory neurons skin through activation protease-activated receptor 1. may be key why so common AD because S. commonly overgrows this owing deficient antimicrobial from epidermis cutaneous microbiome. Increased role microbes provides increased opportunities for safely improving treatment disorder. Atopic (AD) typically occurs during infancy childhood, affecting up 20% children 5% adults many industrialized countries (Weidinger et al., 2018Weidinger Beck L.A. Bieber T. Kabashima K. Irvine A.D. dermatitis.Nat Rev Dis Primers. 2018; 4: 1Google Scholar). Chronic associated with impaired QOL avoidance social interaction (Yosipovitch 2023Yosipovitch G. Kim B. Luger Lerner E. Metz M. Adiri R. al.Similarities differences peripheral pain pathways [epub ahead print].J Allergy Clin Immunol. 2023; https://doi.org/10.1016/j.jaci.2023.10.034Google disorder referred as rashes, phrase reflects patients observed prior any apparent signs inflammation. Itch an important element progression disease. Scratching behavior triggered promotes further barrier disruption There also abundant indirect evidence critical AD. In infants, lesions appear predominantly on dorsal extremities face then shift ventral surfaces trunk age. pattern follows physical ability maturing infant scratch these areas body. addition, report symptoms improve rapidly after initiation anti–IL-4Ra therapy, occurring 2 days start therapy preceding improvement several weeks (Silverberg 2020Silverberg J.I. Yosipovitch Simpson E.L. B.S. Wu J.J. Eckert L. al.Dupilumab results early sustained improvements adolescents moderate severe dermatitis: analysis randomized phase 3 studies SOLO 1 2, ADOL, CHRONOS.J Am Acad Dermatol. 2020; 82: 1328-1336Google Understanding treating therefore goal care active ongoing area investigation. pathogenesis complex remains incompletely understood. Host genetic abnormalities such sequence variants FLG and/or other genes contribute epidermal major risk factors but not causative themselves Defects host immune system, including activating allelic IL-4 (Hershey 1997Hershey G.K. Friedrich M.F. Esswein Thomas M.L. Chatila T.A. association atopy gain-of-function mutation alpha subunit interleukin-4 receptor.N Engl J Med. 1997; 337: 1720-1725Google Scholar), promote rare. Several large-scale GWASs have identified multiple loci AD, account only minority afflicted (Brown, 2021Brown S.J. What we learned GWAS dermatitis?.J Invest 2021; 141: 19-22Google now best understood holobiome, which recognizes function depends cells community bacteria live within body (Burger Gallo, 2023Burger Gallo R.L. Host-microbiome interactions holobiome dermatitis.J 151: 1236-1238Google universally caused abnormalities, suggests driven how its microbiome interact. infectious defined Koch's postulates, almost all change number strains some populate particular, epidermidis overgrow most produce gene products damage barrier, type inflammatory response, influence composition (Saheb Kashaf 2023Saheb Harkins C.P. Deming C. Joglekar P. Conlan Holmes C.J. al.Staphylococcal diversity individual global scale.Cell Microbe. 31: 578-592.e6Google These species defect release adequate amounts peptides cathelicidins β-defensins lack normally would fight against survival pathogenic (Nakatsuji 2023Nakatsuji Brinton S.L. Cavagnero K.J. O'Neill A.M. Chen Y. Dokoshi al.Competition between commensal enables aureus.Cell Rep. 42112494Google just sensation attributed at least part nonpeptidergic exist subgroups possess different receptors response specific chemical entities (puritogens). One group unique G protein-coupled (GPCRs) respond puritogens IL-31 brain natriuretic peptide (Cevikbas 2014Cevikbas F. Wang X. Akiyama Kempkes Savinko Antal A. al.A neuron-expressed mediates T helper cell-dependent itch: involvement TRPV1 TRPA1.J 2014; 133: 448-460Google Other GPCRs include histamine H1/4R (PARs) PAR2. PAR2 thought activated proteases released keratinocytes kallikreins mast tryptase (Ui 2006Ui H. Andoh Lee J.B. Nojima Kuraishi Potent pruritogenic action mediated PAR-2 anti-pruritic effect nafamostat mesilate mice.Eur Pharmacol. 2006; 530: 172-178Google Type cytokines direct (Oetjen 2017Oetjen L.K. Mack M.R. Feng J. Whelan T.M. Niu Guo al.Sensory co-opt classical signaling mediate chronic itch.Cell. 2017; 171: 217-228.e13Google IL-13 recently shown act enhance signals human root ganglia (DRG) model (Miron 2022Miron Miller P.E. Hughes Indersmitten E.A. Cevikbas Mechanistic insights into antipruritic effects lebrikizumab, anti-IL-13 mAb.J 2022; 150: 690-700Google complicated observations (Cohen 2019Cohen J.A. Edwards T.N. Liu A.W. Hirai Jones al.Cutaneous TRPV1+ protective innate 17 anticipatory immunity.Cell. 2019; 178: 919-932.e14Google prevailing paradigm had could result itch. Inflammation due IL-31, indirectly (Datsi 2021Datsi Steinhoff Ahmad Alam Buddenkotte Interleukin-31: "itchy" cytokine therapy.Allergy. 76: 2982-2997Google endogenous proteases. Alternatively, neural stimulation might occur first, consequence scratching cytokines. Thus, supports either From unclear what play itch–scratch–inflammation cycle. A study Deng 2023Deng Costa Blake Choi Chandrabalan Yousuf M.S. al.aureus drives scratch-induced protease-PAR1 axis.Cell. 186: 5375-5393.e25Google Scholar answered question provided more complete suffer pruritus (Figure 1). Knowing high correlation lesional sites, tested possibility induce epicutaneous application mice. To assess was studied using iBOB (infrared box) track bouts enable monitoring spontaneous alloknesis (touch-induced itch). demonstrated topical back mice induced robust scratching, itch-induced exacerbated similar seen contrast, subcutaneous infection did alloknesis, thus demonstrating importance location bacterial illustrating difference excessive colonization surface, characteristic deep tissue infection, frequently rarer often pain. Unexpectedly, previously known mechanisms. Mast (Dong Dong, 2018Dong Dong Peripheral central mechanisms itch.Neuron. 98: 482-494Google lacking were still itchy exposure. IL-36 Myd88 basophils ruled out knockout studies. IL-4, IL-13, relevant (Garcovich 2021Garcovich Maurelli Gisondi Peris Girolomoni distinctive feature inflammation.Vaccines (Basel). 9: 303Google involved aureus–induced Because triggers arise endogenously alter aureus, produced investigated their contribution alloknesis. They started mutations blocked agr quorum sensing. system virulence regulator responds extracellular autoinducing signal when reached, leading enhanced expression toxins exoenzymes (Jenul Horswill, 2019Jenul Horswill A.R. Regulation virulence.Microbiol Spectr. 7https://doi.org/10.1128/microbiolspec.GPP3-0031-2018Google clinically necessary achieved absolute abundance being (Williams 2019Williams S.K. Zaramela L.S. Khalil Todd D.A. Winter H.L. al.Quorum sensing protects injury dermatitis.Sci Transl 11eaat8329Google Activation increases alpha-toxin production, phenol soluble modulin (PSM) infections (Blake 2018Blake Baral Voisin Lubkin Pinho-Ribeiro F.A. Adams K.L. al.Staphylococcus produces pore-forming neuronal silenced QX-314.Nat Commun. 37Google Scholar; Chiu 2013Chiu I.M. Heesters B.A. Ghasemlou N. Von Hehn C.A. Zhao Tran al.Bacteria activate modulate inflammation.Nature. 2013; 501: 52-57Google However, inactivation PSMs no Considering pathology Scholar) success outbreak methicillin-resistant partially (Ramirez 2020Ramirez Beenken K.E. Byrum S.D. Tackett A.J. Shaw L.N. Gimza B.D. al.SarA plays predominant controlling production diverse clinical isolates LAC UAMS-1.Virulence. 11: 1738-1762Google Rom 2017Rom J.S. Atwood D.N. Meeker D.G. Loughran Spencer H.J. al.Impact regulatory biofilm formation USA300 strain murine bacteremia model.Virulence. 8: 1776-1790Google Zielinska 2011Zielinska A.K. Joo H.S. Mrak Griffin L.M. Luong T.T. al.Defining strain-dependent impact Staphylococcal accessory (sarA) phenotype aureus.J Bacteriol. 2011; 193: 2948-2958Google evaluated enzymes Most secrete 10 functions, nutrient acquisition, penetration, evasion 2016Nakatsuji T.H. Two Chun K.A. Narala Geha R.S. exploits defects expression.J 2016; 136: 2192-2200Google Tam Torres, 2019Tam Torres V.J. secreted enzymes.Microbiol 7https://doi.org/10.1128/microbiolspec.GPP3-0039-2018Google (serine sspa), metalloprotease (aureolysin [aur]), cysteine (staphopain staphopain B), 6 serine protease-like proteins positively regulated Through systematic single combination mutants, dependence protease. encoding (sspa) found upregulated mouse time frames occurrences, sspa samples. Notably, injection intradermal cheek injections drove damage, collectively solely sufficient phenotypes. cell tryptases PARs, next hypothesized sense binds activates PAR1, driving Specific cleavage assays mass spectrometry confirmed additional PAR4. DRGs, express PAR1. Mice PAR1 (F2r−/−) failed activation. inhibitor TLCK antagonist vorapaxar prevented V8-induced calcium influx neurons. Small interfering RNA targeting eliminated neuroimmune presence Finally, inhibition reduced narrowing phenotypes somewhat surprising. over 50 years ago (Drapeau 1972Drapeau G.R. Boily Houmard Purification properties Biol Chem. 1972; 247: 6720-6726Google endopeptidase used extensively protein structure field specifically cleave glutamate residues. Although factor (Frey 2021Frey Chaput D. Insight pathodegradome 35108930Google 2004Shaw Golonka Potempa Foster regulation aureus.Microbiology (Reading). 2004; 217-228Google exactly pathology. actions, self-cleave surface (McGavin 1997McGavin M.J. Zahradka Rice Scott J.E. Modification fibronectin binding protease.Infect Immun. 65: 2621-2628Google targets purified enzyme dysfunction applied mice, inducing IgE responses (Hirasawa 2010Hirasawa Takai Nakamura Mitsuishi Gunawan Suto causes dysfunction.J 2010; 130: 614-617Google examining proteolytic activity isolated lesions, Aur (Miedzobrodzki 2002Miedzobrodzki Kaszycki Bialecka Kasprowicz Proteolytic colonized acute-phase dermatitis.Eur Microbiol Infect Dis. 2002; 21: 269-276Google Interestingly, zymogen aur (Drapeau, 1978Drapeau Role precursor staphylococcal protease.J 1978; 607-613Google mutants model, suggesting unknown factors, potentially relying metalloproteases. findings open new overall holobiome. How requires study. Not heavily possible ways. Could V8–PAR-1 treat AD? Indeed, therapeutic use inhibitors investigation dermatology, focus diseases Rosacea (Two 2014Two Hata T.R. Nakatsuji Coda A.B. Kotol P.F. W. al.Reduction correlates improved rosacea severity small, pilot inhibitor.J 134: 1143-1145Google Netherton syndrome (Liddle 2021Liddle Beneton V. Benson Bingham Bouillot Boullay potent selective Kallikrein-5 delivers pharmacological syndrome.J 2272-2279Google diseases, viral pathogens HIV, current suggest benefits. treatments anti–-IL-4Ra rapid similarly (Callewaert 2020Callewaert Knight Kosciolek Vrbanac al.IL-4Ralpha blockade dupilumab decreases microbial 140: 191-202.e7Google Perhaps microbes. We beginning understand full extent health. Richard Gallo: http://orcid.org/0000-0002-6187-2991 Alexander Horswill: http://orcid.org/0000-0002-5568-0096 RLG cofounder, consultant, receives income, equity holder MatriSys Bioscience. remaining author states conflict interest. Grants NIHU01AI52038 (RG), UM1AI151958 R01AI153185 (AH AND RG), R01AR07082 (RG) Conceptualization: RLG, ARH; Writing – Original Draft Preparation: Review Editing: ARH

Language: Английский

---

Mast cell–sensory neuron crosstalk in allergic diseases

Journal of Allergy and Clinical Immunology, Journal Year: 2024, Volume and Issue: 153(4), P. 939 - 953

Published: Feb. 17, 2024

Language: Английский

---

Lebrikizumab: First Approval

Drugs, Journal Year: 2024, Volume and Issue: 84(3), P. 347 - 353

Published: Feb. 23, 2024

Language: Английский

---

Lebrikizumab for the Treatment of Moderate-to-Severe Atopic Dermatitis

American Journal of Clinical Dermatology, Journal Year: 2023, Volume and Issue: 24(5), P. 753 - 764

Published: June 2, 2023

Atopic dermatitis (AD) is a common, heterogeneous, inflammatory skin disorder characterized by chronic or relapsing eczematous lesions with intense pruritus and discomfort. Affected patients often experience significant impairment in their quality of life, the treatment moderate-to-severe AD forms remains challenging. In past few decades, increasing knowledge on pathogenesis has driven development novel targeted therapies. Interleukin (IL)-13 plays central pleiotropic role pathogenesis, contributing directly indirectly to epidermal barrier disfunction, type-2 inflammation, dysbiosis, fibrosis, itch response. For this reason, agents selectively targeting IL-13, such as lebrikizumab, emerged potential therapy for AD. This article reviews current evidence about lebrikizumab management The phase II III trials seem corroborate efficacy AD, shown improvement Eczema Area Severity Index, body surface area, scores. Also, demonstrated favorable safety tolerability profiles, majority experiencing no adverse events. Lebrikizumab seems be promising emerging biological agent More data long-term safety, head-to-head comparisons other agents, real-world will help clarify its place

Language: Английский

---

How to get rid of itching

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 243, P. 108355 - 108355

Published: Feb. 3, 2023

Language: Английский

---

Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape‐strips and biopsies

Allergy, Journal Year: 2023, Volume and Issue: 79(1), P. 80 - 92

Published: Aug. 14, 2023

Abstract Background Our knowledge of etiopathogenesis atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping a minimally invasive, nonscarring technique to collect samples. Methods To construct global AD transcriptomic profile comparing tape‐strips whole‐skin we performed RNA‐seq on biopsies taken the lesional 20 moderate‐to‐severe patients controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 false discovery rate <0.05. Results We detected 4104 (2513 Up; 1591 Down) 1273 (546 727 DEGs in versus controls, respectively. Although both techniques captured dysregulation key immune genes, showed higher FCHs for innate immunity (IL‐1B, IL‐8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), Th17 (CCL20, CXCL1) products, while upregulation Th22 (IL‐22, S100As) dermal cytokines (IFN‐γ, CCL26). Itch‐related (IL‐31, TRPV3) preferentially tape‐strips. Epidermal barrier abnormalities techniques, terminal differentiation defects (FLG2, PSORS1C2) better represented epidermal hyperplasia changes (KRT16, MKI67) biopsies. Conclusions Tape‐strips capture overlapping but distinct features molecular signature, suggesting their respective utility monitoring specific AD‐related immune, itch, clinical trials longitudinal studies.

Language: Английский

---

Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Oct. 5, 2023

Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that elevated in These neuronal cytokine were found to be required several murine models itch. Prior exposure either IL-4 or IL-33 increased their response subsequent chemical pruritogens mice but has not been previously examined humans. The objective the present study was determine if stimulation sensitizes sensory future stimuli fully human ex vivo system.We measured calcium flux from dorsal root ganglia cultures cadaveric donors following transient cytokines. We also effect on changes gene expression by RNA sequencing.Type (IL-4, IL-33) capable sensitizing both histaminergic nonhistaminergic stimuli. Sensitization observed after only h pruritogen incubation. rapid small subset directly dependent presence extracellular calcium. IL-13 induced common signature upregulated genes 24 unique non-type inflammatory stimuli.This provides evidence peripheral neuron sensitization as well broad transcriptomic effects ganglia. studies identify overlapping roles these neurons.

Language: Английский

---

The translational revolution of itch

Neuron, Journal Year: 2022, Volume and Issue: 110(14), P. 2209 - 2214

Published: April 20, 2022

The ability to sense the environment is essential survival and primary purpose of somatosensory nervous system. However, despite its highly conserved nature, sensation itch has been historically overlooked, importance in medicine underappreciated. Herein, we highlight how fundamental discoveries, coupled rapid successes new therapeutics, have placed biology at forefront a translational revolution field somatosensation beyond.

Language: Английский

---

Managing Atopic Dermatitis with Lebrikizumab – The Evidence to Date

Clinical Cosmetic and Investigational Dermatology, Journal Year: 2022, Volume and Issue: Volume 15, P. 1065 - 1072

Published: June 1, 2022

Atopic dermatitis is a prevalent, inflammatory skin disease that presents with an eczematous, itchy rash. As of late, there have been many emerging monoclonal antibody inhibitor and small molecule therapies changed the course eczema treatment. One treatments in pipeline for atopic interleukin 13 inhibitor, lebrikizumab. has identified as pro-inflammatory cytokine immunological cascade eczema, it thought lebrikizumab can be great treatment choice patients dermatitis. Lebrikizumab currently being investigated several studies. Thus far, found to efficacious; particular, rapid response pruritus improvement demonstrated early 2 days. Additionally, well tolerated acceptable safety profile, reports suggesting are decreased risks infection when compared dupilumab. In this review, we aim summarize current understanding terms mechanism action, preclinical pharmacology, pharmacokinetics metabolism, efficacy safety, drug indications.

Language: Английский

---

Critical Players and Therapeutic Targets in Chronic Itch

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9935 - 9935

Published: Sept. 1, 2022

Chronic itch is one of the most prominent clinical characteristics diverse systematic diseases. It a devastating sensation in pathological Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and causes escalate to being top challenges healthcare. Humanized antibodies against IL-13, IL-4, IL-31 proved effective treatment itch-associated atopic dermatitis but remain be validated There still satisfactory anti-itch therapeutics available itch-related neuropeptides including GRP, BNP, SST, CGRP, SP. newly identified potential targets OSM, NMB, glutamate, periostin, Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies been successfully performed on antagonists these proteins their receptors animal models. Their translational interventions humans need evaluated. great importance summarize compare emerging knowledge pathways promote development novel therapeutics. goal this review analyze different physiologies pathophysiologies mediators, whilst assessing suitability as discussing future

Language: Английский

---