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BP180 dysfunction triggers spontaneous skin inflammation in mice

ABSTRACT: BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in 2 maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic 3 mutations in Junctional Epidermolysis Bullosa (JEB) or autoantibody insult in Bullous Pemphigoid 4 (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 5 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-6 dysfunctional mouse strain and found that mice lacking functional BP180 (termed ΔNC16A) 7 developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin 8 barrier, infiltrating immune cells, elevated serum IgE levels and increased expression of thymic 9 stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but 10 dependent on increased expression of TSLP by keratinocytes. Our data provide the first direct 11 evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and 12 BP180 dysfunction leads to a TSLP mediated itch.

ORGANISM(S): Mus musculus

PROVIDER: GSE112235 | GEO | 2018/03/23

REPOSITORIES: GEO

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Project description:Animal models have enhanced our understanding of the pathogenesis of autoimmune diseases. For these models, genetically identical, inbred mice have commonly been used. Different inbred mouse strains, however, show a high variability in disease manifestation. Identifying the factors that influence this disease variability could provide unrecognized insights into pathogenesis. We established a novel antibody transfer-induced model of epidermolysis bullosa acquisita (EBA), an autoimmune disease characterized by (muco)-cutaneous blistering caused by anti-type VII collagen (COL7) autoantibodies. Blistering after anti-COL7 IgG (directed against the von-Willebrand-factor A like domain 2) transfer showed clear variability among inbred mouse strains; i.e. severe cutaneous blistering and inflammation in C57Bl/6J, and absence of skin lesions in MRL/MpJ mice. The transfer of anti-COL7 IgG into irradiated, EBA-resistant MRL/MpJ mice, rescued by transplantation with bone marrow from EBA-susceptible B6.AK-H2k mice, induced blistering. To the contrary, irradiated EBA-susceptible B6.AK-H2k mice that were rescued using MRL/MpJ bone marrow were devoid of blistering. In vitro, immune complex activation of neutrophils from C57Bl/6J or MRL/MpJ mice showed an impaired ROS release from the latter, whereas no differences were observed after PMA activation. This finding was paralleled by divergent expression profiles of immune-complex activated neutrophils from either C57Bl/6J or MRL/MpJ mice. Collectively, we demonstrate that radiosensitive cells determine the varying extent of skin inflammation and blistering in the end-stage effector phase of EBA. We used microarray to differentiate between the molecular response for the immune complex stimulated neutrophils in MRL/MpJ and C57Bl/6J mice To unravel the molecular basis for the different response to immune complex (IC) stimulation between MRL/MpJ and C57Bl/6J mice, the cells were activated using IC, and differential expression using microarray was compared between resting or activated neutrophils from MRL/MpJ or C57Bl/6J mice.

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BP180 dysfunction triggers spontaneous skin inflammation in mice

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