THE ROLE OF BP180 IN GRANULOPOIESIS AND NLRP3 INFLAMMASOME ACTIVATION IN BULLOUS PEMPHIGOID
Public Deposited- Last Modified
- June 7, 2019
- Creator
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Lin, Lin
- Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
- Abstract
- BP180 (also called collagen XVII) is a hemidesmosomal protein. Autoantibodies directly against it cause bullous pemphigoid (BP). Gene mutations of BP180 result in generalized atrophic benign epidermolysis bullosa (GABEB). BP patients’ autoantibodies primarily recognize NC16A domain of BP180; however, there is no cross reactivity between human NC16A and mouse homologue termed NC14A. To investigate the pathogenesis of BP and identify new functions of BP180, we established humanized BP180NC16A (NC16A) mice, and subsequently NC16A domain truncated (ΔNC16A) mice. In ΔNC16A mice, we discovered a novel function of BP180: this cell-matrix adhesion molecule may work on a signaling pathway regulating granulopoiesis. It was recently reported that GABEB or other types of epidermolysis bullosa (EB) patients have granulocyte infiltration and eosinophilia. Abnormal granulopoiesis was also observed in ΔNC16A mice in addition to skin abnormality. The affected granulopoiesis originated in the stromal cell compartment of the bone marrow because transplantation of bone marrow from ΔNC16 mice into wild-type mice corrected the myeloid hyperplasia. In addition, ΔNC16 mice at 4 weeks of age also developed myeloid hyperplasia without any skin lesions. K14 Cre-driven, skin-specific ΔNC16 mice exhibit similar skin lesions as ΔNC16A mice, but had normal granulopoiesis. We demonstrated that NC16A deletion induces NF-kB signaling pathway activation that leads to elevated G-CSF secretion in bone marrow and blood. G-CSF regulates granulopoiesis in bone marrow. These findings provide a mechanism for clinical relevant pathophysiological observation in BP and Junctional Epidermolysis Bullosa (JEB). NC16A mice injected with anti-NC16A autoantibodies develop skin disease that closely mimics the clinical, immunological and histological features of human BP. Previous works have shown that pathological autoantibodies against NC16A, when binding to the target on basal keratinocytes, trigger complement activation to generate C5a. C5a binding to the C5a receptor on mast cells leads to TNFα release. Mast cell recruitment of polymorphonuclear neutrophils is required for disease. However, the mechanisms by which mast cells recruit neutrophils to the antibody-binding sites are not completely known. We used mice lacking key components of NLRP’s inflammasome to test whether mast cell-released TNF-α would act on keratinocyte as first signal and pathogenic IgG binding to BP180 as a second signal to activate NLRP3 inflammasome in basal keratinocyte. We found that pathogenic antibody-induced BP depends on NLRP3 activation, leading to IL-1β release and subsequent neutrophil recruitment. Furthermore, we showed that IL-1R antagonist, Anakinra, could be an effective drug to treat experimental BP. In this study, we suggest a molecular mechanism for mast cells recruitment of neutrophils in experimental BP. More importantly, our findings identify potential new therapeutic targets for treatment of BP. The findings described in this dissertation explored a novel function of BP180 and its mechanism, which would benefit for these symptom-related diseases. BP180 functional deficiency in bone marrow stromal cells results in highly activated NF-kB signaling pathway that leads to increased G-CSF production and more granulocytes in bone marrow and periphery. Our findings also refine our understanding of the pathogenesis of BP by demonstrating that NLRP3 inflammasome activation in keratinocytes is critical for BP, especially for mast cell recruitment of neutrophils to the skin. These findings elucidate a molecular mechanism that would provide a potential treatment for BP.
- Date of publication
- August 2016
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Vilen, Barbara J.
- Liu, Zhi
- Arnold, Roland
- Ting, Jenny P.-Y.
- Miao, Edward
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2016
- Language
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This work has no parents.
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