Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin
Background Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells. Methods Back skin of C57BL/6 mice was trea...
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| Veröffentlicht in: | Allergy (Copenhagen) 2024-01, Vol.79 (1), p.128-141 |
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| creator | Rinaldi, Arturo O. Li, Manru Barletta, Elena D'Avino, Paolo Yazici, Duygu Pat, Yagiz Ward, Siobhan Burla, Daniel Tan, Ge Askary, Nima Larsson, Rasmus Bost, Jeremy Babayev, Huseyn Dhir, Raja Gaudenzio, Nicolas Akdis, Mubeccel Nadeau, Kari Akdis, Cezmi A. Mitamura, Yasutaka |
| description | Background
Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells.
Methods
Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA‐seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6‐h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin.
Results
Detergent‐treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose–response in EIS. The RNA‐seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion‐related proteins, such as epithelial cell adhesion molecule and contactin‐1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model.
Conclusion
The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.
Household laundry detergents led to reduced electrical impedance, indicating impaired skin barrier. RNA‐seq and targeted multiplex protein analyses in skin biopsy demonstrated that laundry detergents disrupted several major pathways involved in the skin barrier and induced inflammation. Laundry detergents and SDS caused barrier damage in ex vivo human skin.Abbreviations: ACVRL1, activin A receptor like type; CCL, C‐C motif chemokine ligand; CLSTN2, calsyntenin‐2; CNTN1, contactin‐1; EPCAM, epithelial cell adhesion molecule; FASTL3, follistatin‐related protein 3; IL1B, interleukin 1 beta; IL6, interleukin 6; PBS, phosphate‐buffered saline; RNA‐seq, RNA sequ |
| doi_str_mv | 10.1111/all.15891 |
| format | Article |
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Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells.
Methods
Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA‐seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6‐h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin.
Results
Detergent‐treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose–response in EIS. The RNA‐seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion‐related proteins, such as epithelial cell adhesion molecule and contactin‐1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model.
Conclusion
The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.
Household laundry detergents led to reduced electrical impedance, indicating impaired skin barrier. RNA‐seq and targeted multiplex protein analyses in skin biopsy demonstrated that laundry detergents disrupted several major pathways involved in the skin barrier and induced inflammation. Laundry detergents and SDS caused barrier damage in ex vivo human skin.Abbreviations: ACVRL1, activin A receptor like type; CCL, C‐C motif chemokine ligand; CLSTN2, calsyntenin‐2; CNTN1, contactin‐1; EPCAM, epithelial cell adhesion molecule; FASTL3, follistatin‐related protein 3; IL1B, interleukin 1 beta; IL6, interleukin 6; PBS, phosphate‐buffered saline; RNA‐seq, RNA sequencing; SDS, sodium dodecyl sulfate</description><identifier>ISSN: 0105-4538</identifier><identifier>ISSN: 1398-9995</identifier><identifier>EISSN: 1398-9995</identifier><identifier>DOI: 10.1111/all.15891</identifier><identifier>PMID: 37766519</identifier><language>eng</language><publisher>Denmark: Blackwell Publishing Ltd</publisher><subject>Atopy ; Biopsy ; Cell adhesion & migration ; Cell adhesion molecules ; Cell differentiation ; Contactin ; Cytokines ; Detergents ; electrical impedance spectroscopy ; epithelial barrier ; Epithelial cells ; ex vivo human skin ; Inflammatory diseases ; Interleukin 1 ; Interleukin 6 ; Keratinization ; Laundry ; laundry detergents ; Proteins ; Proteomics ; Ribonucleic acid ; RNA ; skin inflammation ; Sodium lauryl sulfate ; Spectroscopy ; Tight junctions ; transepidermal water loss</subject><ispartof>Allergy (Copenhagen), 2024-01, Vol.79 (1), p.128-141</ispartof><rights>2023 The Authors. published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.</rights><rights>2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.</rights><rights>2023. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3881-2a5b15e868726fd269f72beabb4b4df6158fd67c4db7dfc20c2ce1625172a41f3</citedby><cites>FETCH-LOGICAL-c3881-2a5b15e868726fd269f72beabb4b4df6158fd67c4db7dfc20c2ce1625172a41f3</cites><orcidid>0000-0002-2146-2955 ; 0000-0003-0026-8739 ; 0000-0002-8431-4140 ; 0000-0001-6389-9285 ; 0000-0001-8967-3866 ; 0000-0003-0554-9943 ; 0000-0001-8020-019X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fall.15891$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fall.15891$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37766519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rinaldi, Arturo O.</creatorcontrib><creatorcontrib>Li, Manru</creatorcontrib><creatorcontrib>Barletta, Elena</creatorcontrib><creatorcontrib>D'Avino, Paolo</creatorcontrib><creatorcontrib>Yazici, Duygu</creatorcontrib><creatorcontrib>Pat, Yagiz</creatorcontrib><creatorcontrib>Ward, Siobhan</creatorcontrib><creatorcontrib>Burla, Daniel</creatorcontrib><creatorcontrib>Tan, Ge</creatorcontrib><creatorcontrib>Askary, Nima</creatorcontrib><creatorcontrib>Larsson, Rasmus</creatorcontrib><creatorcontrib>Bost, Jeremy</creatorcontrib><creatorcontrib>Babayev, Huseyn</creatorcontrib><creatorcontrib>Dhir, Raja</creatorcontrib><creatorcontrib>Gaudenzio, Nicolas</creatorcontrib><creatorcontrib>Akdis, Mubeccel</creatorcontrib><creatorcontrib>Nadeau, Kari</creatorcontrib><creatorcontrib>Akdis, Cezmi A.</creatorcontrib><creatorcontrib>Mitamura, Yasutaka</creatorcontrib><title>Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin</title><title>Allergy (Copenhagen)</title><addtitle>Allergy</addtitle><description>Background
Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells.
Methods
Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA‐seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6‐h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin.
Results
Detergent‐treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose–response in EIS. The RNA‐seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion‐related proteins, such as epithelial cell adhesion molecule and contactin‐1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model.
Conclusion
The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.
Household laundry detergents led to reduced electrical impedance, indicating impaired skin barrier. RNA‐seq and targeted multiplex protein analyses in skin biopsy demonstrated that laundry detergents disrupted several major pathways involved in the skin barrier and induced inflammation. Laundry detergents and SDS caused barrier damage in ex vivo human skin.Abbreviations: ACVRL1, activin A receptor like type; CCL, C‐C motif chemokine ligand; CLSTN2, calsyntenin‐2; CNTN1, contactin‐1; EPCAM, epithelial cell adhesion molecule; FASTL3, follistatin‐related protein 3; IL1B, interleukin 1 beta; IL6, interleukin 6; PBS, phosphate‐buffered saline; RNA‐seq, RNA sequencing; SDS, sodium dodecyl sulfate</description><subject>Atopy</subject><subject>Biopsy</subject><subject>Cell adhesion & migration</subject><subject>Cell adhesion molecules</subject><subject>Cell differentiation</subject><subject>Contactin</subject><subject>Cytokines</subject><subject>Detergents</subject><subject>electrical impedance spectroscopy</subject><subject>epithelial barrier</subject><subject>Epithelial cells</subject><subject>ex vivo human skin</subject><subject>Inflammatory diseases</subject><subject>Interleukin 1</subject><subject>Interleukin 6</subject><subject>Keratinization</subject><subject>Laundry</subject><subject>laundry detergents</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>skin inflammation</subject><subject>Sodium lauryl sulfate</subject><subject>Spectroscopy</subject><subject>Tight junctions</subject><subject>transepidermal water loss</subject><issn>0105-4538</issn><issn>1398-9995</issn><issn>1398-9995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1kMtKxDAUQIMoOj4W_oAU3OiiTpI2jy5FfMGAG12HtLkZo2k6Ji0yf2901IVgNpcLh8PNQeiY4AuS31x7f0GYbMgWmpGqkWXTNGwbzTDBrKxZJffQfkovGGNBG7yL9iohOGekmSF7N0wJngdvCq-nYOK6MDBCXEIYU2FcitNqLFodo4NYuDDCMrpxXehg8mamDvKwXve9Ht0Q8lL0n8Yv4HnqdSjSqwuHaMdqn-Doex6gp5vrx6u7cvFwe391uSi7SkpSUs1awkByKSi3hvLGCtqCbtu6rY3l-ZPWcNHVphXGdhR3tAPCKSOC6prY6gCdbbyrOLxNkEbVu9SB9zpAPktRKTCphKxYRk__oC_DFEO-TuVIEmNeyzpT5xuqi0NKEaxaRdfruFYEq8_4KsdXX_Eze_JtnNoezC_5UzsD8w3w7jys_zepy8Vio_wAln2PWA</recordid><startdate>202401</startdate><enddate>202401</enddate><creator>Rinaldi, Arturo O.</creator><creator>Li, Manru</creator><creator>Barletta, Elena</creator><creator>D'Avino, Paolo</creator><creator>Yazici, Duygu</creator><creator>Pat, Yagiz</creator><creator>Ward, Siobhan</creator><creator>Burla, Daniel</creator><creator>Tan, Ge</creator><creator>Askary, Nima</creator><creator>Larsson, Rasmus</creator><creator>Bost, Jeremy</creator><creator>Babayev, Huseyn</creator><creator>Dhir, Raja</creator><creator>Gaudenzio, Nicolas</creator><creator>Akdis, Mubeccel</creator><creator>Nadeau, Kari</creator><creator>Akdis, Cezmi A.</creator><creator>Mitamura, Yasutaka</creator><general>Blackwell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2146-2955</orcidid><orcidid>https://orcid.org/0000-0003-0026-8739</orcidid><orcidid>https://orcid.org/0000-0002-8431-4140</orcidid><orcidid>https://orcid.org/0000-0001-6389-9285</orcidid><orcidid>https://orcid.org/0000-0001-8967-3866</orcidid><orcidid>https://orcid.org/0000-0003-0554-9943</orcidid><orcidid>https://orcid.org/0000-0001-8020-019X</orcidid></search><sort><creationdate>202401</creationdate><title>Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin</title><author>Rinaldi, Arturo O. ; Li, Manru ; Barletta, Elena ; D'Avino, Paolo ; Yazici, Duygu ; Pat, Yagiz ; Ward, Siobhan ; Burla, Daniel ; Tan, Ge ; Askary, Nima ; Larsson, Rasmus ; Bost, Jeremy ; Babayev, Huseyn ; Dhir, Raja ; Gaudenzio, Nicolas ; Akdis, Mubeccel ; Nadeau, Kari ; Akdis, Cezmi A. ; Mitamura, Yasutaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3881-2a5b15e868726fd269f72beabb4b4df6158fd67c4db7dfc20c2ce1625172a41f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Atopy</topic><topic>Biopsy</topic><topic>Cell adhesion & migration</topic><topic>Cell adhesion molecules</topic><topic>Cell differentiation</topic><topic>Contactin</topic><topic>Cytokines</topic><topic>Detergents</topic><topic>electrical impedance spectroscopy</topic><topic>epithelial barrier</topic><topic>Epithelial cells</topic><topic>ex vivo human skin</topic><topic>Inflammatory diseases</topic><topic>Interleukin 1</topic><topic>Interleukin 6</topic><topic>Keratinization</topic><topic>Laundry</topic><topic>laundry detergents</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>skin inflammation</topic><topic>Sodium lauryl sulfate</topic><topic>Spectroscopy</topic><topic>Tight junctions</topic><topic>transepidermal water loss</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rinaldi, Arturo O.</creatorcontrib><creatorcontrib>Li, Manru</creatorcontrib><creatorcontrib>Barletta, Elena</creatorcontrib><creatorcontrib>D'Avino, Paolo</creatorcontrib><creatorcontrib>Yazici, Duygu</creatorcontrib><creatorcontrib>Pat, Yagiz</creatorcontrib><creatorcontrib>Ward, Siobhan</creatorcontrib><creatorcontrib>Burla, Daniel</creatorcontrib><creatorcontrib>Tan, Ge</creatorcontrib><creatorcontrib>Askary, Nima</creatorcontrib><creatorcontrib>Larsson, Rasmus</creatorcontrib><creatorcontrib>Bost, Jeremy</creatorcontrib><creatorcontrib>Babayev, Huseyn</creatorcontrib><creatorcontrib>Dhir, Raja</creatorcontrib><creatorcontrib>Gaudenzio, Nicolas</creatorcontrib><creatorcontrib>Akdis, Mubeccel</creatorcontrib><creatorcontrib>Nadeau, Kari</creatorcontrib><creatorcontrib>Akdis, Cezmi A.</creatorcontrib><creatorcontrib>Mitamura, Yasutaka</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Allergy (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rinaldi, Arturo O.</au><au>Li, Manru</au><au>Barletta, Elena</au><au>D'Avino, Paolo</au><au>Yazici, Duygu</au><au>Pat, Yagiz</au><au>Ward, Siobhan</au><au>Burla, Daniel</au><au>Tan, Ge</au><au>Askary, Nima</au><au>Larsson, Rasmus</au><au>Bost, Jeremy</au><au>Babayev, Huseyn</au><au>Dhir, Raja</au><au>Gaudenzio, Nicolas</au><au>Akdis, Mubeccel</au><au>Nadeau, Kari</au><au>Akdis, Cezmi A.</au><au>Mitamura, Yasutaka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin</atitle><jtitle>Allergy (Copenhagen)</jtitle><addtitle>Allergy</addtitle><date>2024-01</date><risdate>2024</risdate><volume>79</volume><issue>1</issue><spage>128</spage><epage>141</epage><pages>128-141</pages><issn>0105-4538</issn><issn>1398-9995</issn><eissn>1398-9995</eissn><abstract>Background
Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells.
Methods
Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA‐seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6‐h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin.
Results
Detergent‐treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose–response in EIS. The RNA‐seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion‐related proteins, such as epithelial cell adhesion molecule and contactin‐1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model.
Conclusion
The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.
Household laundry detergents led to reduced electrical impedance, indicating impaired skin barrier. RNA‐seq and targeted multiplex protein analyses in skin biopsy demonstrated that laundry detergents disrupted several major pathways involved in the skin barrier and induced inflammation. Laundry detergents and SDS caused barrier damage in ex vivo human skin.Abbreviations: ACVRL1, activin A receptor like type; CCL, C‐C motif chemokine ligand; CLSTN2, calsyntenin‐2; CNTN1, contactin‐1; EPCAM, epithelial cell adhesion molecule; FASTL3, follistatin‐related protein 3; IL1B, interleukin 1 beta; IL6, interleukin 6; PBS, phosphate‐buffered saline; RNA‐seq, RNA sequencing; SDS, sodium dodecyl sulfate</abstract><cop>Denmark</cop><pub>Blackwell Publishing Ltd</pub><pmid>37766519</pmid><doi>10.1111/all.15891</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-2146-2955</orcidid><orcidid>https://orcid.org/0000-0003-0026-8739</orcidid><orcidid>https://orcid.org/0000-0002-8431-4140</orcidid><orcidid>https://orcid.org/0000-0001-6389-9285</orcidid><orcidid>https://orcid.org/0000-0001-8967-3866</orcidid><orcidid>https://orcid.org/0000-0003-0554-9943</orcidid><orcidid>https://orcid.org/0000-0001-8020-019X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Allergy (Copenhagen), 2024-01, Vol.79 (1), p.128-141 |
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| source | Wiley Online Library Journals Frontfile Complete |
| subjects | Atopy Biopsy Cell adhesion & migration Cell adhesion molecules Cell differentiation Contactin Cytokines Detergents electrical impedance spectroscopy epithelial barrier Epithelial cells ex vivo human skin Inflammatory diseases Interleukin 1 Interleukin 6 Keratinization Laundry laundry detergents Proteins Proteomics Ribonucleic acid RNA skin inflammation Sodium lauryl sulfate Spectroscopy Tight junctions transepidermal water loss |
| title | Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin |
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