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Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice

Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of hu...

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Autores principales: Robida, Piper A., Chumanevich, Alena P., Gandy, Alexa Orr, Fuseler, John W., Nagarkatti, Prakash, Nagarkatti, Mitzi, Oskeritzian, Carole A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346072/
https://www.ncbi.nlm.nih.gov/pubmed/34360617
http://dx.doi.org/10.3390/ijms22157851
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author Robida, Piper A.
Chumanevich, Alena P.
Gandy, Alexa Orr
Fuseler, John W.
Nagarkatti, Prakash
Nagarkatti, Mitzi
Oskeritzian, Carole A.
author_facet Robida, Piper A.
Chumanevich, Alena P.
Gandy, Alexa Orr
Fuseler, John W.
Nagarkatti, Prakash
Nagarkatti, Mitzi
Oskeritzian, Carole A.
author_sort Robida, Piper A.
collection PubMed
description Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metabolism [Cer synthases (CerS) and ceramidases (Asah1/Asah2)], which revealed augmented CerS 4, 5 and 6 and Asah1. Given the overall pro-apoptotic nature of Cer, local apoptosis was assessed, then quantified using novel morphometric measurements of cleaved caspase (Casp)-3-restricted immunofluorescence signal in skin samples. Apoptosis was induced in response to OVA. Because apoptosis may occur downstream of endoplasmic reticulum (ER) stress, we measured markers of ER stress-induced apoptosis and found elevated skin-associated CHOP protein upon OVA treatment. We previously substantiated the importance of mast cells (MC) in initiating early skin inflammation. OVA-induced Cer increase and local apoptosis were prevented in MC-deficient mice; however, they were restored following MC reconstitution. We propose that the MC/Cer axis is an essential pathogenic feature of pre-lesional AD, whose targeting may prevent disease development.
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spelling pubmed-83460722021-08-07 Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice Robida, Piper A. Chumanevich, Alena P. Gandy, Alexa Orr Fuseler, John W. Nagarkatti, Prakash Nagarkatti, Mitzi Oskeritzian, Carole A. Int J Mol Sci Article Atopic dermatitis (AD or eczema) is the most common chronic inflammatory skin disorder worldwide. Ceramides (Cer) maintain skin barrier functions, which are disrupted in lesional skin of AD patients. However, Cer status during the pre-lesional phase of AD is not well defined. Using a variation of human AD-like preclinical model consisting of a 7-day topical exposure to ovalbumin (OVA), or control, we observed elevation of Cer C16 and C24. Skin mRNA quantification of enzymes involved in Cer metabolism [Cer synthases (CerS) and ceramidases (Asah1/Asah2)], which revealed augmented CerS 4, 5 and 6 and Asah1. Given the overall pro-apoptotic nature of Cer, local apoptosis was assessed, then quantified using novel morphometric measurements of cleaved caspase (Casp)-3-restricted immunofluorescence signal in skin samples. Apoptosis was induced in response to OVA. Because apoptosis may occur downstream of endoplasmic reticulum (ER) stress, we measured markers of ER stress-induced apoptosis and found elevated skin-associated CHOP protein upon OVA treatment. We previously substantiated the importance of mast cells (MC) in initiating early skin inflammation. OVA-induced Cer increase and local apoptosis were prevented in MC-deficient mice; however, they were restored following MC reconstitution. We propose that the MC/Cer axis is an essential pathogenic feature of pre-lesional AD, whose targeting may prevent disease development. MDPI 2021-07-22 /pmc/articles/PMC8346072/ /pubmed/34360617 http://dx.doi.org/10.3390/ijms22157851 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Robida, Piper A.
Chumanevich, Alena P.
Gandy, Alexa Orr
Fuseler, John W.
Nagarkatti, Prakash
Nagarkatti, Mitzi
Oskeritzian, Carole A.
Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title_full Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title_fullStr Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title_full_unstemmed Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title_short Skin Mast Cell-Driven Ceramides Drive Early Apoptosis in Pre-Symptomatic Eczema in Mice
title_sort skin mast cell-driven ceramides drive early apoptosis in pre-symptomatic eczema in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346072/
https://www.ncbi.nlm.nih.gov/pubmed/34360617
http://dx.doi.org/10.3390/ijms22157851
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