Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

Suzanne L. Cassel; John R. Janczy; Xinyu BingShruti P. WilsonAlicia K. OlivierJesse E. OteroYoichiro IwakuraDmitry M. ShayakhmetovAlexander G. BassukYousef Abu-AmerKim A. BrogdenTrudy L. BurnsFayyaz S. SutterwalaPolly J. Ferguson

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Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

机译：Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

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Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmomice resulted in a significant reduction in the time to onset of disease aswell as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第3期|1072-1077|共6页
作者
Suzanne L. Cassel; John R. Janczy; Xinyu BingShruti P. WilsonAlicia K. OlivierJesse E. OteroYoichiro IwakuraDmitry M. ShayakhmetovAlexander G. BassukYousef Abu-AmerKim A. BrogdenTrudy L. BurnsFayyaz S. SutterwalaPolly J. Ferguson;
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作者单位

Department of Pediatrics, College of Dentistry, University of Iowa, Iowa City, IA 52242;

Inflammation Program, College of Dentistry, University of Iowa, Iowa City, IA 52242;

Department of Internal Medicine, College of Dentistry, University of Iowa, Iowa City, IA 52242Department of Pathology, College of Dentistry, University of Iowa, Iowa City, IA 52242Department of Orthopedics, College of Dentistry, University of Iowa, Iowa City, IA 52242Research Institute for Biomedical Sciences, Tokyo University of Science Yamasaki 2669, Noda, Chiba 278-0022, JapanDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110Dows Institute for Dental Research and Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, IA 52242;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
chronic osteomyelitis; innate immunity;

Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

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