PMC:3279418 / 1758-4724 JSONTXT

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There are accumulations of eosinophils, neutrophils and macrophages in the skin of Sharpincpdm/Sharpincpdm mutant mice (hereafter referred to as cpdm mice) associated with increased expression of Th2 cytokines in the skin and in the supernatants of activated splenocytes [5]. The mice have an impaired delayed type hypersensitivity response and decreased secretion of IFNγ [5], indicating a defect in Th1 immune responses and a bias towards a Th2 immune response. Systemic treatment of cpdm mice with recombinant IL12 caused complete remission of the dermatitis [5]. Neutralization of IL5 by antibody treatment or crosses with IL5-deficient mice reduced the number of circulating and cutaneous eosinophils, but failed to reduce the onset and severity of the dermatitis [6].\nRecently, three independent groups identified SHARPIN as an essential component of the linear ubiquitin chain assembly complex (LUBAC) that regulates TNFα-induced canonical NF-κB signaling [7]–[9]. SHARPIN-deficient mouse embryonic fibroblast (MEF) were sensitized to TNFα-induced apoptosis and cell death was implicated as a factor in the dermatitis of cpdm mice [7]–[9].\nDendritic cells (DC) have a sentinel role in sensing pathogen or danger signals and initiate and direct activation of the adaptive immune response [10]. Activated and mature DC can carry processed antigenic peptides, migrate to lymphoid organs, and induce T-cell-mediated immune responses or tolerance. DC direct the differentiation of CD4+ T cells, and hence the type of immune response, through the selective secretion of cytokines. We hypothesized that defective cytokine secretion by DC contributed to the Th2-biased inflammatory phenotype in SHARPIN-deficient mice. The studies reported here found that lack of SHARPIN protein in BMDC caused defective expression of pro-inflammatory mediators and impaired NF-κB activation upon ligand stimulation. The ability of cpdm BMDC to stimulate Th1 cytokine production in allogeneic CD4+ T cells was compromised. Taken together, these results reveal that SHARPIN is a novel regulatory molecule in DC biology and suggest that the dysregulated function of SHARPIN-deficient DC plays a role in the cpdm 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