This study identifies IL-3 as a potent inducer of RANKL expression in human basophils, suggesting them to interact with bone physiology and activation of immune cells. IgER-dependent and IgER-independent stimuli modulate the IL-3-mediated RANKL expression in a time- and stimulus-dependent fashion.

SummaryBackground In contrast to eosinophils and neutrophils, the regulation of the lifespan of human basophils is poorly defined, with the exception of the potent anti-apoptotic effect of IL-3 that also promotes pro-inflammatory effector functions and phenotypic changes. Type I IFNs (IFN-a, IFN-b), which are well known for their anti-viral activities, have the capacity to inhibit allergic inflammation. Objective To elucidate whether type I IFNs have the potential to abrogate the lifespan and/or effector functions of human basophils. Methods We cultured human basophils, and for comparison, eosinophils and neutrophils, with IL-3, interferons, FasL and TRAIL, alone or in combination, and studied cell survival, effector functions and signalling pathways involved. Results Despite an identical pattern of early signalling in basophils, eosinophils and neutrophils in response to different types of interferons, only basophils displayed enhanced apoptosis after type I IFN treatment. IFN-c prolonged survival of eosinophils but did not affect the lifespan of basophils. IFN-a-mediated apoptosis required STAT1-STAT2 heterodimers and the contribution of constitutive p38 MAPK activity. Whereas the death ligands FasL and TRAIL-induced apoptosis in basophils per se, IFN-a-mediated apoptosis did neither involve autocrine TRAIL signalling nor did it sensitize basophils to FasL-induced apoptosis. However, IFN-a and FasL displayed an additive effect in killing basophils. Interestingly, IL-3, which protected basophils from IFN-a-, TRAIL-or FasL-mediated apoptosis, did not completely block the additive effect of combined IFN-a and FasL treatment. Moreover, we demonstrate that IFN-a suppressed IL-3-induced release of IL-8 and IL-13. In contrast to IFN-a-mediated apoptosis, these inhibitory effects of IFN-a were not dependent on p38 MAPK signalling. Conclusions and Clinical Relevance Our study defines the unique and granulocyte-typespecific inhibitory and pro-apoptotic function of type I IFNs and their cooperation with death ligands in human blood basophils, which may be relevant for the anti-allergic properties of type I IFNs.

our results, and further proteomics and functional studies are needed to elucidate the role these genes play in relation to changes in Staphylococcus species and skin barrier dysfunction in general.As a general conclusion, we postulate that the explanation for AD flare development and exacerbation is a complex interaction between the skin microbiota, barrier, and immune system. Interaction points between different components of human skin might be the key to development of therapeutic approaches to allergic skin diseases. Guttman-Yassky E, et al. Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. J Allergy Clin Immunol 2016;138:336-49. 4. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol 2017;139: 1723-34. 5. Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 2006;155:680-7. 6. Esaki H, Ewald DA, Ungar B, Rozenblit M, Zheng X, Xu H, et al. Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol 2015;135:153-63. 7. Williams MR, Gallo RL. The role of the skin microbiome in atopic dermatitis. Curr Allergy Asthma Rep 2015;15:65. 8. Suarez-Farinas M, Ungar B, Correa da Rosa J, Ewald DA, Rozenblit M, Gonzalez J, et al. RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications. J Allergy Clin Immunol 2015;135:1218-27. 9. Clark RT, Hope A, Lopez-Fraga M, Schiller N, Lo DD. Bacterial particle endocytosis by epithelial cells is selective and enhanced by tumor necrosis factor receptor ligands.

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