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Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling

SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of seconda...

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Autores principales: Potter, Christopher S., Wang, Zhe, Silva, Kathleen A., Kennedy, Victoria E., Stearns, Timothy M., Burzenski, Lisa, Shultz, Leonard D., HogenEsch, Harm, Sundberg, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897490/
https://www.ncbi.nlm.nih.gov/pubmed/24465642
http://dx.doi.org/10.1371/journal.pone.0085666
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author Potter, Christopher S.
Wang, Zhe
Silva, Kathleen A.
Kennedy, Victoria E.
Stearns, Timothy M.
Burzenski, Lisa
Shultz, Leonard D.
HogenEsch, Harm
Sundberg, John P.
author_facet Potter, Christopher S.
Wang, Zhe
Silva, Kathleen A.
Kennedy, Victoria E.
Stearns, Timothy M.
Burzenski, Lisa
Shultz, Leonard D.
HogenEsch, Harm
Sundberg, John P.
author_sort Potter, Christopher S.
collection PubMed
description SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(−/−) mice, which lack mature B and T cells, were crossed with Sharpin(−/−) mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(−/−) mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(−/−) mice. Double homozygous Sharpin(−/−), Il4ra(−/−) mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(−/−), Il4ra(−/−) double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(−/−), Il4ra(−/−) mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(−/−) mice and this was maintained in Sharpin(−/−), Il4ra(−/−) mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti-inflammatory role in SHARPIN-deficient mice.
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spelling pubmed-38974902014-01-24 Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling Potter, Christopher S. Wang, Zhe Silva, Kathleen A. Kennedy, Victoria E. Stearns, Timothy M. Burzenski, Lisa Shultz, Leonard D. HogenEsch, Harm Sundberg, John P. PLoS One Research Article SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(−/−) mice, which lack mature B and T cells, were crossed with Sharpin(−/−) mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(−/−) mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(−/−) mice. Double homozygous Sharpin(−/−), Il4ra(−/−) mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(−/−), Il4ra(−/−) double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(−/−), Il4ra(−/−) mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(−/−) mice and this was maintained in Sharpin(−/−), Il4ra(−/−) mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti-inflammatory role in SHARPIN-deficient mice. Public Library of Science 2014-01-21 /pmc/articles/PMC3897490/ /pubmed/24465642 http://dx.doi.org/10.1371/journal.pone.0085666 Text en © 2014 Potter et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Potter, Christopher S.
Wang, Zhe
Silva, Kathleen A.
Kennedy, Victoria E.
Stearns, Timothy M.
Burzenski, Lisa
Shultz, Leonard D.
HogenEsch, Harm
Sundberg, John P.
Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title_full Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title_fullStr Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title_full_unstemmed Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title_short Chronic Proliferative Dermatitis in Sharpin Null Mice: Development of an Autoinflammatory Disease in the Absence of B and T Lymphocytes and IL4/IL13 Signaling
title_sort chronic proliferative dermatitis in sharpin null mice: development of an autoinflammatory disease in the absence of b and t lymphocytes and il4/il13 signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897490/
https://www.ncbi.nlm.nih.gov/pubmed/24465642
http://dx.doi.org/10.1371/journal.pone.0085666
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