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Inhibition of NF-?B signaling retards eosinophilic dermatitis in SHARPIN-deficient mice.

ABSTRACT: The NF-?B pathway performs pivotal roles in diverse physiological processes such as immunity, inflammation, proliferation, and apoptosis. NF-?B is kept inactive in the cytoplasm through association with inhibitors (I?B), and translocates to the nucleus to activate its target genes after the I?Bs are phosphorylated and degraded. Here, we demonstrate that loss of function of SHANK-associated RH domain interacting protein (SHARPIN) leads to activation of NF-?B signaling in skin, resulting in the development of an idiopathic hypereosinophilic syndrome (IHES) with eosinophilic dermatitis in C57BL/KaLawRij-Sharpin(cpdm)/RijSunJ mice, and clonal expansion of B-1 B cells and CD3(+)CD4(-)CD8(-) T cells. Transcription profiling in skin revealed constitutive activation of classical NF-?B pathways, predominantly by overexpressed members of IL1 family. Compound-null mutants for both the IL1 receptor accessory protein (Il1rap(tm1Roml)) and SHARPIN (Sharpin(cpdm)) resulted in mice having decreased skin disease severity. Inhibition of I?BA degradation by the proteasome inhibitor bortezomib alleviated the dermatitis in Sharpin(cpdm) mice. These results indicate that absence of SHARPIN causes IHES with eosinophilic dermatitis by NF-?B activation, and bortezomib may be an effective treatment for skin problems of IHES.

SUBMITTER: Liang Y

PROVIDER: S-EPMC3071979 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Inhibition of NF-κB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice.

Liang Yanhua Y Seymour Rosemarie E RE Sundberg John P JP

The Journal of investigative dermatology 20100902 1

The NF-κB pathway performs pivotal roles in diverse physiological processes such as immunity, inflammation, proliferation, and apoptosis. NF-κB is kept inactive in the cytoplasm through association with inhibitors (IκB), and translocates to the nucleus to activate its target genes after the IκBs are phosphorylated and degraded. Here, we demonstrate that loss of function of SHANK-associated RH domain interacting protein (SHARPIN) leads to activation of NF-κB signaling in skin, resulting in the de ...[more]

PMID: 20811394

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Project 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.

Dataset Information

Inhibition of NF-?B signaling retards eosinophilic dermatitis in SHARPIN-deficient mice.

Publications

Inhibition of NF-κB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice.

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