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Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status

Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status
Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status
Background: acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored.Objectives: hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models.Methods: explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models.Results: bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins.Conclusions: these findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema.
0007-0963
396-406
Clayton, Kalum
499fec32-9297-45bd-9207-5ba699734844
Holbrook, Daniel J.
903d4d8a-08b1-43fc-bb74-3632b22c5283
Vallejo, Andres
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Porter, Gemma
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Sirvent, Sofia
afc59842-b3c7-4c9d-8176-f7d137dd6a87
Davies, James
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Pople, Jenny
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Lim, Fei Ling
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Christodoulides, Myron
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Polak, Marta E.
e0ac5e1a-7074-4776-ba23-490bd4da612d
Ardern-Jones, Michael R.
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Clayton, Kalum
499fec32-9297-45bd-9207-5ba699734844
Holbrook, Daniel J.
903d4d8a-08b1-43fc-bb74-3632b22c5283
Vallejo, Andres
294fca39-0187-47b4-90ad-cadc7b888830
Porter, Gemma
fc6bde09-079f-461f-bdb8-9c2690b21039
Sirvent, Sofia
afc59842-b3c7-4c9d-8176-f7d137dd6a87
Davies, James
a93b4fc9-80a2-4620-ada6-c12f05c5ee38
Pople, Jenny
0ec34f58-beb7-4596-92a4-653b0b5bc5a1
Lim, Fei Ling
5d565505-ce8e-40e3-8418-3e9875255629
Christodoulides, Myron
eba99148-620c-452a-a334-c1a52ba94078
Polak, Marta E.
e0ac5e1a-7074-4776-ba23-490bd4da612d
Ardern-Jones, Michael R.
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Clayton, Kalum, Holbrook, Daniel J., Vallejo, Andres, Porter, Gemma, Sirvent, Sofia, Davies, James, Pople, Jenny, Lim, Fei Ling, Christodoulides, Myron, Polak, Marta E. and Ardern-Jones, Michael R. (2023) Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status. British Journal of Dermatology, 188 (3), 396-406. (doi:10.1093/bjd/ljac088).

Record type: Article

Abstract

Background: acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored.Objectives: hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models.Methods: explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models.Results: bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins.Conclusions: these findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema.

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Accepted/In Press date: 5 November 2022
e-pub ahead of print date: 17 November 2022
Published date: 22 February 2023
Additional Information: Funding Information: This work was supported by the Medical Research Council DTP PhD Scheme and iCASE partnership with Unilever (scheme no. MR/N014308/1). M.E.P. is funded by the Wellcome Trust (Sir Henry Dale Fellowship, Wellcome Trust grant no. 10937/Z/15/Z). Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of British Association of Dermatologists.

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Local EPrints ID: 476987
URI: http://eprints.soton.ac.uk/id/eprint/476987
ISSN: 0007-0963
PURE UUID: faafd93a-27a2-4890-bacb-bdc2d4d664a6
ORCID for Kalum Clayton: ORCID iD orcid.org/0000-0002-1143-3931
ORCID for Myron Christodoulides: ORCID iD orcid.org/0000-0002-9663-4731
ORCID for Michael R. Ardern-Jones: ORCID iD orcid.org/0000-0003-1466-2016

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Date deposited: 23 May 2023 16:33
Last modified: 17 Mar 2024 03:10

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Contributors

Author: Kalum Clayton ORCID iD
Author: Daniel J. Holbrook
Author: Andres Vallejo
Author: Gemma Porter
Author: Sofia Sirvent
Author: James Davies
Author: Jenny Pople
Author: Fei Ling Lim
Author: Marta E. Polak

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