title: Opposing effects on immune function and skin barrier regulation by the proteasome inhibitor bortezomib in an allergen-induced eczema model.
abstract: Proteasome inhibition (PI) has been reported to interfere with antibody-driven autoimmune diseases. The impact of PI on the allergic immune response and on skin diseases like atopic dermatitis (AD) has not been thoroughly explored, however. Here, we examined whether the PI bortezomib interferes with the allergic immune response and the severity of AD by using an established mouse model of allergen-driven dermatitis, to which bortezomib was applied after the establishment of systemic sensitization to ovalbumin. The treatment indeed resulted in a remarkable decrease in total and allergen-specific plasma cells/antibody-secreting cells, as evidenced by flow cytometry and ELISpot, respectively. This was accompanied by rapid reductions in serum antibody titres, including a prominent reduction of the IgE isotype. CD4+ and CD8+ cells were greatly diminished in lesional skin on immunohistological staining. The impressive effects at the level of immune modulation did not result in any improvement in the eczema, however. Following up on this unexpected result, we found that the skin itself was susceptible to bortezomib, by which it was instructed to lower the expression of critical skin barrier genes, especially transglutaminase-1 and filaggrin. Together, bortezomib eliminates plasma cells and decreases immunoglobulin responses, including allergenic IgE. Although anti-inflammatory effects are detectable in the skin, counter-regulatory effects from PI on resident skin cells likely undermine improvement in the eczema. These results caution against the therapeutic use of bortezomib for inflammatory skin disorders, which are characterized by inherently impaired barrier function, especially AD.
authors.affiliation: Department of Dermatology und Allergology, Allergie-Centrum-Charité, CCM, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Mudnakudu Nagaraju
authors.forename: Magda
authors.initials: M
authors.lastname: Babina
authors.forename: Margitta
authors.initials: M
authors.lastname: Worm
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D003876:Dermatitis, Atopic / Q000188:drug therapy; D004195:Disease Models, Animal; D004485:Eczema / Q000188:drug therapy*; D005260:Female; D007107:Immune System / Q000502:physiology*; D007073:Immunoglobulin E / Q000097:blood; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use*; D012867:Skin / Q000473:pathology
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D007073:Immunoglobulin E; D000069286:Bortezomib
keywords: antibody-secreting cells; atopic dermatitis; bortezomib (Velcade®); proteasome inhibition; skin barrier