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.