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

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 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-κB 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 IκBA 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-κB activation, and bortezomib may be an effective treatment for skin problems of IHES.