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postgraduate thesis: The role of IL-17 in the pathogenesis and therapeutic intervention of experimental Sjögren's syndrome

TitleThe role of IL-17 in the pathogenesis and therapeutic intervention of experimental Sjögren's syndrome
Authors
Advisors
Advisor(s):Lu, LWong, CCL
Issue Date2018
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Xiao, F. [肖凡]. (2018). The role of IL-17 in the pathogenesis and therapeutic intervention of experimental Sjögren's syndrome. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractSjögren’s syndrome (SS) is a chronic autoimmune disease characterized by dry mouth and dry eyes with inflammation in the exocrine glands. Currently, the pathogenesis of SS is still unclear. Although previous studies have revealed that IL-17 and Th17 cells are involved in SS pathogenesis, how IL-17 affects salivary gland (SG) hypofunction and whether targeting Th17 cells is effective in SS remaine largely unclear. In this study, a murine experimental SS (ESS) model was established, which recapitulated key symptoms of SS patients including hyposalivation, glandular inflammation and serological hallmarks of autoantibody production. Both IL-17 knockout (KO) and IL-17 receptor C (IL-17RC) KO mice exhibited ameliorated ESS development when compared with wild type (WT) mice. Moreover, WT mice with ESS displayed increased numbers of IL-17-producing cells in SG tissues and draining lymph nodes compared with naïve control mice. In addition, the chimeric mice with IL-17RC deficiency restricted in non-hematopoietic cells exhibited improved saliva secretion and ameliorated SG tissue inflammation compared with WT controls, indicating that IL-17 modulates ESS development through targeting non-hematopoietic cells, most likely SG epithelial cells. Notably, acini from ESS mice displayed decreased acetylcholine-induced calcium movement whereas IL-17 diminished the acetylcholine-induced store-operated calcium entry (SOCE) in cultured primary SG epithelial cells. Moreover, immunofluorescence staining and Western blot analysis revealed that IL-17 treatment reduced expression of transient receptor potential channel 1 (TRPC1), a key ion channel for calcium influx in SOCE. Furthermore, IL-17 enhanced IκB-zeta expression whereas knockdown of IκB-zeta increased TRPC1 expression, indicating that IL-17 regulates TRPC1 via inducing IκB-zeta expression. Therefore, the results showed that IL-17 decreased acetylcholine-induced SOCE by down-regulating TRPC1 expressions and thus directly contributed to SG dysfunction in ESS development. Although extensive studies on the pathogenesis of SS have achieved significant progress in the past decade, effective therapies for SS patients are still lacking. Recent studies have shown that proteasome, especially the subunit of immunoproteasome low-molecular-weight protein 7 (LMP7), is involved in modulating T cell functions. However, it remains unknown whether proteasome inhibitor can target Th17 cells and serves as an effective therapeutic approach for SS. In this study, Bortezomib (BTZ), the first proteasome inhibitor approved for treating multiple myeloma, was found to effectively attenuate ESS development by inhibiting Th17 responses. Th17 cells from ESS mice exhibited high levels of LMP7 expression while BTZ treatment markedly suppressed Th17 differentiation and proliferation in culture. Notably, BTZ-treated ESS mice displayed improved saliva secretion and ameliorated SG tissue destruction when compared with vehicle-treated counterparts. In addition, BTZ-treated ESS mice showed significantly decreased Th17 cells in peripheral lymphoid organs. Furthermore, immunized IL-17 KO mice transferred with WT naïve CD4+ T cells showed salivary dysfunction while BTZ treatment profoundly suppressed donor cell-derived Th17 responses and ameliorated SG hypofunction. Taken together, those findings have revealed a critical role of IL-17 in SG dysfunctions and showed the therapeutic effects of targeting Th17 cells by proteasome inhibitor in ESS mice, which may contribute to the validation of targeting IL-17 and Th17 cells as therapeutic approaches for the treatment of SS patients.
DegreeDoctor of Philosophy
SubjectInterleukin-17
Sjogren's syndrome
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/279714

 

DC FieldValueLanguage
dc.contributor.advisorLu, L-
dc.contributor.advisorWong, CCL-
dc.contributor.authorXiao, Fan-
dc.contributor.author肖凡-
dc.date.accessioned2019-12-10T10:04:37Z-
dc.date.available2019-12-10T10:04:37Z-
dc.date.issued2018-
dc.identifier.citationXiao, F. [肖凡]. (2018). The role of IL-17 in the pathogenesis and therapeutic intervention of experimental Sjögren's syndrome. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/279714-
dc.description.abstractSjögren’s syndrome (SS) is a chronic autoimmune disease characterized by dry mouth and dry eyes with inflammation in the exocrine glands. Currently, the pathogenesis of SS is still unclear. Although previous studies have revealed that IL-17 and Th17 cells are involved in SS pathogenesis, how IL-17 affects salivary gland (SG) hypofunction and whether targeting Th17 cells is effective in SS remaine largely unclear. In this study, a murine experimental SS (ESS) model was established, which recapitulated key symptoms of SS patients including hyposalivation, glandular inflammation and serological hallmarks of autoantibody production. Both IL-17 knockout (KO) and IL-17 receptor C (IL-17RC) KO mice exhibited ameliorated ESS development when compared with wild type (WT) mice. Moreover, WT mice with ESS displayed increased numbers of IL-17-producing cells in SG tissues and draining lymph nodes compared with naïve control mice. In addition, the chimeric mice with IL-17RC deficiency restricted in non-hematopoietic cells exhibited improved saliva secretion and ameliorated SG tissue inflammation compared with WT controls, indicating that IL-17 modulates ESS development through targeting non-hematopoietic cells, most likely SG epithelial cells. Notably, acini from ESS mice displayed decreased acetylcholine-induced calcium movement whereas IL-17 diminished the acetylcholine-induced store-operated calcium entry (SOCE) in cultured primary SG epithelial cells. Moreover, immunofluorescence staining and Western blot analysis revealed that IL-17 treatment reduced expression of transient receptor potential channel 1 (TRPC1), a key ion channel for calcium influx in SOCE. Furthermore, IL-17 enhanced IκB-zeta expression whereas knockdown of IκB-zeta increased TRPC1 expression, indicating that IL-17 regulates TRPC1 via inducing IκB-zeta expression. Therefore, the results showed that IL-17 decreased acetylcholine-induced SOCE by down-regulating TRPC1 expressions and thus directly contributed to SG dysfunction in ESS development. Although extensive studies on the pathogenesis of SS have achieved significant progress in the past decade, effective therapies for SS patients are still lacking. Recent studies have shown that proteasome, especially the subunit of immunoproteasome low-molecular-weight protein 7 (LMP7), is involved in modulating T cell functions. However, it remains unknown whether proteasome inhibitor can target Th17 cells and serves as an effective therapeutic approach for SS. In this study, Bortezomib (BTZ), the first proteasome inhibitor approved for treating multiple myeloma, was found to effectively attenuate ESS development by inhibiting Th17 responses. Th17 cells from ESS mice exhibited high levels of LMP7 expression while BTZ treatment markedly suppressed Th17 differentiation and proliferation in culture. Notably, BTZ-treated ESS mice displayed improved saliva secretion and ameliorated SG tissue destruction when compared with vehicle-treated counterparts. In addition, BTZ-treated ESS mice showed significantly decreased Th17 cells in peripheral lymphoid organs. Furthermore, immunized IL-17 KO mice transferred with WT naïve CD4+ T cells showed salivary dysfunction while BTZ treatment profoundly suppressed donor cell-derived Th17 responses and ameliorated SG hypofunction. Taken together, those findings have revealed a critical role of IL-17 in SG dysfunctions and showed the therapeutic effects of targeting Th17 cells by proteasome inhibitor in ESS mice, which may contribute to the validation of targeting IL-17 and Th17 cells as therapeutic approaches for the treatment of SS patients.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshInterleukin-17-
dc.subject.lcshSjogren's syndrome-
dc.titleThe role of IL-17 in the pathogenesis and therapeutic intervention of experimental Sjögren's syndrome-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2019-
dc.identifier.mmsid991044081527903414-

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