한빛사논문
- 조회349
Wonyong Lee,1 Deborah L Stone,1 Patrycja Hoffmann,1 Sofia Rosenzweig,1 Wanxia Li Tsai,2 Massimo Gadina,2 Tina Romeo,1 Chyi-Chia Richard Lee,3 Davide Randazzo,4 Pallavi Pimpale Chavan,1 Kalpana Manthiram,5 Scott Canna,6 Yong Hwan Park,7 Amanda K Ombrello,1 Ivona Aksentijevich,1 Daniel L Kastner,1 Jae Jin Chae1
1Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
2Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
3Translational Autoinflammatory Diseases Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
4Office of Science and Technology, Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
5Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
6Division of Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
7Department of Microbiology, Ajou University School of Medicine, Suwon, Gyeonggido, Korea (the Republic of)
Correspondence to Dr Daniel L Kastner
Abstract
Objectives: To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1.
Methods: Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients.
Results: The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γ priming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γ was abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN-γ-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement.
Conclusion: PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γ positive feedback loop that drives PAPA disease activity and is a target for JAK inhibition.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-04-29)
- 국내+국외 연구진
- 생명과학 > 면역학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
