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 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.
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Christopher S
CS
Potter
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Zhe
Z
Wang
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Kathleen A
KA
Silva
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Victoria E
VE
Kennedy
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Timothy M
TM
Stearns
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Lisa
L
Burzenski
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Leonard D
LD
Shultz
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
Harm
H
Hogenesch
The Jackson Laboratory, Bar Harbor, Maine, United States of America ; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, United States of America.
John P
JP
Sundberg
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000276:immunology / Q000473:pathology*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
D002352:Carrier Proteins; D018398:Homeodomain Proteins; D018793:Interleukin-13; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C554944:Sipl1 protein, mouse; C064658:RAG-1 protein