Analysis of the mechanism of autoinflammatory disorder induction due to proteasome dysfunction

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokushima
• Principal Investigator: SASAKI Yuki 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (50454757)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: PRAAS / PSMB8 / CXCL9 / CXCL10

Outline of Final Research Achievements

Mutations in immunoproteasome subunits lead to immunoproteasome dysfunction, which causes proteasome-associated autoinflammatory syndromes (PRAAS). It remains unclear, however, how immunoproteasome dysfunction leads to inflammatory symptoms. Here, we established mice harboring a mutation in Psmb8 (Psmb8-KI mice). Psmb8-KI mice showed higher susceptibility to imiquimod-induced skin inflammation (IMS). The skins where imiquimod was painted also expressed the Cxcl9 and Cxcl10 genes at higher levels in Psmb8-KI than control mice. Deficiency in Cxcr3, the gene encoding the receptor of CXCL9 and CXCL10, in wild-type mice did not change IMS susceptibility, while deficiency in Cxcr3 in Psmb8-KI mice ameliorated IMS. These findings demonstrate that this mutation in Psmb8 leads to hyperactivation of the CXCR3 pathway, which is responsible for the increased susceptibility of Psmb8-KI mice to IMS. These data suggest the CXCR3-CXCL10 axis as a new molecular target for treating PRAAS patients.

Free Research Field

免疫

Academic Significance and Societal Importance of the Research Achievements

プロテアソーム関連自己炎症性症候群PRAASと同様の変異を持つPsmb8ミスセンス変異ノックインマウス(Psmb8-KI)を樹立し解析を行った。PRAASにおいてPSMB8以外のサブユニットの変異も報告されているがPRAASの詳しい発症機構は解明されていない。本研究では免疫プロテアソームの機能破綻がどのように炎症病態を誘導しているかについての 分子機構の一端を明らかにした。今後PSMB8が様々な炎症病態にどのように機能しているかを解明することは慢性炎症性疾患に対する治療法の開発に大きく貢献すると期待できる。