Competition Between Skin Antimicrobial Peptides and Commensal Bacteria in Type 2 Inflammation Enables Survival of S. Aureus

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 May 11

PMID 37167061

Authors

Teruaki Nakatsuji

Samantha L Brinton

Kellen J Cavagnero

Alan M ONeill

Yang Chen

Tatsuya Dokoshi

Anna M Butcher

Olive C Osuoji

Faiza Shafiq

Josh L Espinoza

Christopher L Dupont

Tissa R Hata

Richard L Gallo

Affiliations

Soon will be listed here.

Abstract

During inflammation, the skin deploys antimicrobial peptides (AMPs) yet during allergic inflammation it becomes more susceptible to Staphylococcus aureus. To understand this contradiction, single-cell sequencing of Il4ra mice combined with skin microbiome analysis reveals that lower production of AMPs from interleukin-4 receptor α (IL-4Rα) activation selectively inhibits survival of antibiotic-producing strains of coagulase-negative Staphylococcus (CoNS). Diminished AMPs under conditions of T helper type 2 (Th2) inflammation enable expansion of CoNS strains without antibiotic activity and increase Staphylococcus aureus (S. aureus), recapitulating the microbiome on humans with atopic dermatitis. This response is rescued in Camp mice or after topical steroids, since further inhibition of AMPs enables survival of antibiotic-producing CoNS strains. In conditions of Th17 inflammation, a higher expression of host AMPs is sufficient to directly inhibit S. aureus survival. These results show that antimicrobials produced by the host and commensal bacteria each act to control S. aureus on the skin.

Citing Articles

Do Melanocytes Have a Role in Controlling Epidermal Bacterial Colonisation and the Skin Microbiome?.

Bi O, Caballero-Lima D, Sikkink S, Westgate G, Kauser S, Elies J Exp Dermatol. 2025; 34(3):e70071.

PMID: 40051134 PMC: 11885897. DOI: 10.1111/exd.70071.

Skin microbiome and dermatologic disorders.

Scharschmidt T, Segre J J Clin Invest. 2025; 135(3).

PMID: 39895627 PMC: 11785926. DOI: 10.1172/JCI184315.

Advances in Microbiome-Based Therapeutics for Dermatological Disorders: Current Insights and Future Directions.

Madaan T, Doan K, Hartman A, Gherardini D, Ventrola A, Zhang Y Exp Dermatol. 2024; 33(12):e70019.

PMID: 39641544 PMC: 11663288. DOI: 10.1111/exd.70019.

Novel Peptide Analogues of Valorphin-Conjugated 1,8-Naphthalimide as Photodynamic Antimicrobial Agent in Solution and on Cotton Fabric.

Staneva D, Todorov P, Georgieva S, Peneva P, Grabchev I Molecules. 2024; 29(22).

PMID: 39598810 PMC: 11597154. DOI: 10.3390/molecules29225421.

Large-scale investigation for antimicrobial activity reveals novel defensive species across the healthy skin microbiome.

Nguyen U, Salamzade R, Sandstrom S, Swaney M, Townsend L, Wu S bioRxiv. 2024; .

PMID: 39574598 PMC: 11580923. DOI: 10.1101/2024.11.04.621544.

References

Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang Y, Homey B . Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007; 449(7162):564-9. DOI: 10.1038/nature06116. View

Rosenberg E, Zilber-Rosenberg I . The hologenome concept of evolution after 10 years. Microbiome. 2018; 6(1):78. PMC: 5922317. DOI: 10.1186/s40168-018-0457-9. View

Hinrichsen K, Podschun R, Schubert S, Schroder J, Harder J, Proksch E . Mouse beta-defensin-14, an antimicrobial ortholog of human beta-defensin-3. Antimicrob Agents Chemother. 2008; 52(5):1876-9. PMC: 2346663. DOI: 10.1128/AAC.01308-07. View

Gallo R, Kim K, Bernfield M, Kozak C, Zanetti M, Merluzzi L . Identification of CRAMP, a cathelin-related antimicrobial peptide expressed in the embryonic and adult mouse. J Biol Chem. 1997; 272(20):13088-93. DOI: 10.1074/jbc.272.20.13088. View

Mohanty S, Kamolvit W, Scheffschick A, Bjorklund A, Tovi J, Espinosa A . Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder. Nat Commun. 2022; 13(1):4983. PMC: 9489794. DOI: 10.1038/s41467-022-32636-y. View

Aberg K, Radek K, Choi E, Kim D, Demerjian M, Hupe M . Psychological stress downregulates epidermal antimicrobial peptide expression and increases severity of cutaneous infections in mice. J Clin Invest. 2007; 117(11):3339-49. PMC: 2045593. DOI: 10.1172/JCI31726. View

Byrd A, Deming C, Cassidy S, Harrison O, Ng W, Conlan S . and strain diversity underlying pediatric atopic dermatitis. Sci Transl Med. 2017; 9(397). PMC: 5706545. DOI: 10.1126/scitranslmed.aal4651. View

Marchitto M, Dillen C, Liu H, Miller R, Archer N, Ortines R . Clonal Vγ6Vδ4 T cells promote IL-17-mediated immunity against skin infection. Proc Natl Acad Sci U S A. 2019; 116(22):10917-10926. PMC: 6561199. DOI: 10.1073/pnas.1818256116. View

Trenam C, Blake D, Morris C . Skin inflammation: reactive oxygen species and the role of iron. J Invest Dermatol. 1992; 99(6):675-82. DOI: 10.1111/1523-1747.ep12613740. View

10.

Wertz P . Lipids and the Permeability and Antimicrobial Barriers of the Skin. J Lipids. 2018; 2018:5954034. PMC: 6139190. DOI: 10.1155/2018/5954034. View

11.

Albanesi C, Fairchild H, Madonna S, Scarponi C, De Pita O, Leung D . IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol. 2007; 179(2):984-92. DOI: 10.4049/jimmunol.179.2.984. View

12.

Gotz F, Perconti S, Popella P, Werner R, Schlag M . Epidermin and gallidermin: Staphylococcal lantibiotics. Int J Med Microbiol. 2013; 304(1):63-71. DOI: 10.1016/j.ijmm.2013.08.012. View

13.

Nakatsuji T, Gallo R, Shafiq F, Tong Y, Chun K, Butcher A . Use of Autologous Bacteriotherapy to Treat Staphylococcus aureus in Patients With Atopic Dermatitis: A Randomized Double-blind Clinical Trial. JAMA Dermatol. 2021; . PMC: 8209585. DOI: 10.1001/jamadermatol.2021.1311. View

14.

Alam M, Xie L, Ang C, Fahimi F, Willingham S, Kueh A . Therapeutic blockade of CXCR2 rapidly clears inflammation in arthritis and atopic dermatitis models: demonstration with surrogate and humanized antibodies. MAbs. 2020; 12(1):1856460. PMC: 7757791. DOI: 10.1080/19420862.2020.1856460. View

15.

Ernst C, Staubitz P, Mishra N, Yang S, Hornig G, Kalbacher H . The bacterial defensin resistance protein MprF consists of separable domains for lipid lysinylation and antimicrobial peptide repulsion. PLoS Pathog. 2009; 5(11):e1000660. PMC: 2774229. DOI: 10.1371/journal.ppat.1000660. View

16.

Howell M, Boguniewicz M, Pastore S, Novak N, Bieber T, Girolomoni G . Mechanism of HBD-3 deficiency in atopic dermatitis. Clin Immunol. 2006; 121(3):332-8. DOI: 10.1016/j.clim.2006.08.008. View

17.

Zhang L, Guerrero-Juarez C, Hata T, Bapat S, Ramos R, Plikus M . Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science. 2015; 347(6217):67-71. PMC: 4318537. DOI: 10.1126/science.1260972. View

18.

Gonzalez M, Schaffer J, Orlow S, Gao Z, Li H, Alekseyenko A . Cutaneous microbiome effects of fluticasone propionate cream and adjunctive bleach baths in childhood atopic dermatitis. J Am Acad Dermatol. 2016; 75(3):481-493.e8. PMC: 4992571. DOI: 10.1016/j.jaad.2016.04.066. View

19.

Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A . Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007; 13(8):975-80. DOI: 10.1038/nm1616. View

20.

Boxberger M, Cenizo V, Cassir N, La Scola B . Challenges in exploring and manipulating the human skin microbiome. Microbiome. 2021; 9(1):125. PMC: 8166136. DOI: 10.1186/s40168-021-01062-5. View