Inhibition of NF-kappa B Signaling Retards Eosinophilic Dermatitis in SHARPIN-Deficient Mice

The NF-kappa B pathway performs pivotal roles in diverse physiological processes such as immunity, inflammation, proliferation, and apoptosis. NF-kappa B is kept inactive in the cytoplasm through association with inhibitors (I kappa B), and translocates to the nucleus to activate its target genes after the I kappa 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-kappa 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-kappa 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 kappa 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-kappa B activation, and bortezomib may be an effective treatment for skin problems of IHES.