Seminars in Immunology, Journal Year: 2025, Volume and Issue: 78, P. 101933 - 101933
Published: March 8, 2025
Language: Английский
Science, Journal Year: 2025, Volume and Issue: 387(6733)
Published: Jan. 30, 2025
Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which exacerbates inflammation whether provides benefit to host are largely unknown. We found that was required for skin mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced pain-sensing nociceptors, neuropeptide substance P, receptor MrgprB2. Scratching also increased augmented defense superficial Staphylococcus aureus infection. Thus, activation of nociceptor-driven neuroinflammation, both exacerbated allergic disease provided protection from S. aureus, reconciling seemingly paradoxical role as pathological process evolutionary adaptation.
Language: Английский
Citations
4
Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 815 - 831
Published: April 1, 2024
Language: Английский
Citations
16
Allergy, Journal Year: 2024, Volume and Issue: 79(6), P. 1470 - 1484
Published: Feb. 3, 2024
The skin microbiome is an extensive community of bacteria, fungi, mites, viruses and archaea colonizing the skin. Fluctuations in composition have been observed atopic dermatitis (AD) food allergy (FA), particularly early life, established disease, associated with therapeutics. However, AD a multifactorial disease characterized by barrier aberrations modulated genetics, immunology, environmental influences, thus not sole feature this disease. Future research should focus on mechanistic understanding how early-life microbial shifts may influence FA onset, to guide potential intervention strategies or as biomarkers identify high-risk infants who benefit from possible microbiome-based biotherapeutic strategies. Harnessing microbes biotherapeutics emerging field, but more work needed investigate whether approach can lead sustained clinical responses.
Language: Английский
Citations
12
Journal of Investigative Dermatology, Journal Year: 2024, Volume and Issue: 144(11), P. 2377 - 2398
Published: Aug. 8, 2024
The function of keratinocytes (KCs) to form a barrier and produce cytokines is well-known, but recent progress has revealed many different roles for KCs in regulation skin immunity. In this review, we provide an update on the current understanding how communicate with microbes, immunocytes, neurons, other cells effective immune barrier. We catalog large list genes metabolites that participate host defense discuss mechanisms crosstalk, addressing simultaneously physical barrier, fibroblasts, control signals. Overall, signals sent received by are exciting group therapeutic targets explore treatment dermatologic disorders.
Language: Английский
Citations
12
mBio, Journal Year: 2024, Volume and Issue: 15(5)
Published: March 28, 2024
ABSTRACT Staphylococcus aureus is a Gram-positive pathogen responsible for the majority of skin and soft tissue infections (SSTIs). S. colonizes anterior nares approximately 20%–30% population transiently skin, thereby increasing risk developing SSTIs more serious infections. Current laboratory models that mimic surface environment are expensive, require substantial infrastructure, limit scope bacterial physiology studies under human conditions. To overcome these limitations, we developed cost-effective, open-source, chemically defined media recipe termed skin-like medium (SLM) incorporates key aspects supports growth several staphylococcal species. We utilized SLM to investigate transcriptional response methicillin-resistant (MRSA) following in compared commonly used media. Through RNA-seq analysis, observed upregulation virulence factors, including genes encoding functions involved adhesion, proteolysis, cytotoxicity. further explore findings, conducted quantitative reverse transcription-PCR (qRT-PCR) experiments determine influence composition, pH, temperature on factors adhesion virulence. also demonstrated MRSA primed adhered better corneocytes adhesin-specific phenotypes previously required genetic manipulation. This improved adherence was dependent both acidic pH SLM. These results support potential utility as an vitro model assessing metabolism skin. IMPORTANCE major cause diseases, its increased prevalence colonization present need understand this environment. The work presented here outlines using newly strives replicate demonstrates roles adhesins clumping factor A (ClfA), serine-rich repeat glycoprotein adhesin (SraP), fibronectin binding proteins (Fnbps) corneocyte adherence.
Language: Английский
Citations
10
The Journal of Microbiology, Journal Year: 2024, Volume and Issue: 62(3), P. 181 - 199
Published: March 1, 2024
Language: Английский
Citations
10
Seminars in Immunology, Journal Year: 2025, Volume and Issue: 77, P. 101928 - 101928
Published: Jan. 10, 2025
Language: Английский
Citations
1
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
Citations
8
Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(772)
Published: Nov. 6, 2024
Endometriosis is a debilitating and painful gynecological inflammatory disease affecting up to 15% of women transgender men. Current treatments are ineffective for substantial proportion patients, underscoring the need additional therapies with long-term benefits. Nociceptors release neuropeptides, such as calcitonin gene–related peptide (CGRP), which known shape immunity through neuroimmune communication. Given comorbidity between endometriosis migraine integral role immune cells inflammation in endometriosis, we investigated CGRP-mediated communication endometriosis. Using samples from eight patients nonsurgical mouse model disease, found that human lesions contain both CGRP its coreceptor, receptor activity modifying protein 1 (RAMP1). In mice, nociceptor ablation reduced pain, monocyte recruitment, lesion size, suggesting activation neuropeptide contribute growth pain. Mechanistically, changed phenotype macrophages pro-endometriosis phenotype. CGRP-stimulated demonstrated impaired efferocytosis supported increased endometrial cell RAMP1-dependent manner. Treatment lesion-bearing mice US Food Drug Administration–approved drugs block CGRP-RAMP1 signaling mechanical hyperalgesia, spontaneous size. Together, our data effectiveness underlying cellular mechanisms nonhormonal nonopioid CGRP/RAMP1 blockade targeting this axis may lead clinical benefit
Language: Английский
Citations
7
European Respiratory Review, Journal Year: 2024, Volume and Issue: 33(172), P. 240008 - 240008
Published: April 30, 2024
Neuroimmune recognition and regulation in the respiratory system is a complex highly coordinated process involving interactions between nervous immune systems to detect respond pathogens, pollutants other potential hazards tract. This interaction helps maintain health integrity of system. Therefore, understanding critical maintaining lung developing treatments for diseases. In this review, we summarise projection distribution different types neurons (trigeminal nerve, glossopharyngeal vagus spinal dorsal root sympathetic nerve) We also introduce several cells epithelium that closely interact with nerves (pulmonary neuroendocrine cells, brush solitary chemosensory tastebuds). These are primarily located at key positions tract, where project them, forming neuroepithelial units, thus enhancing ability neural recognition. Furthermore, roles played by these sensing or responding specific pathogens (influenza, severe acute syndrome coronavirus 2, syncytial virus, human metapneumovirus, herpes viruses, Sendai parainfluenza
Language: Английский
Citations
6