Chronic proliferative dermatitis in Sharpin null mice

Development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling

Christopher S. Potter, Zhe Wang, Kathleen A. Silva, Victoria E. Kennedy, Timothy M. Stearns, Lisa Burzenski, Leonard D. Shultz, Harm HogenEsch, John P. Sundberg

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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 antiinflammatory role in SHARPIN-deficient mice.

Original languageEnglish (US)
Article numbere85666
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 21 2014
Externally publishedYes

Fingerprint

Dermatitis
T-cells
Interleukin-13
dermatitis
Interleukin-4
B-lymphocytes
B-Lymphocytes
T-lymphocytes
T-Lymphocytes
Lymphocytes
mice
inflammation
Skin
Inflammation
lymphocytes
skin (animal)
Cytokines
sharpin
Integrins
Liver

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 9, No. 1, e85666, 21.01.2014.

Research output: Contribution to journalArticle

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. In: PLoS One. 2014 ; Vol. 9, No. 1.
@article{68a1b2d49ed040e4a11bfdfab18f8728,
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",
abstract = "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 antiinflammatory role in SHARPIN-deficient mice.",
author = "Potter, {Christopher S.} and Zhe Wang and Silva, {Kathleen A.} and Kennedy, {Victoria E.} and Stearns, {Timothy M.} and Lisa Burzenski and Shultz, {Leonard D.} and Harm HogenEsch and Sundberg, {John P.}",
year = "2014",
month = "1",
day = "21",
doi = "10.1371/journal.pone.0085666",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

TY - JOUR

T1 - Chronic proliferative dermatitis in Sharpin null mice

T2 - Development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling

AU - Potter, Christopher S.

AU - Wang, Zhe

AU - Silva, Kathleen A.

AU - Kennedy, Victoria E.

AU - Stearns, Timothy M.

AU - Burzenski, Lisa

AU - Shultz, Leonard D.

AU - HogenEsch, Harm

AU - Sundberg, John P.

PY - 2014/1/21

Y1 - 2014/1/21

N2 - 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 antiinflammatory role in SHARPIN-deficient mice.

AB - 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 antiinflammatory role in SHARPIN-deficient mice.

UR - http://www.scopus.com/inward/record.url?scp=84906739952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906739952&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0085666

DO - 10.1371/journal.pone.0085666

M3 - Article

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 1

M1 - e85666

ER -