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Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
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SYSNO ASEP 0567400 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation Author(s) Pavliuchenko, Nataliia (UMG-J)
Duric, Iris (UMG-J)
Králová, Jarmila (UMG-J)
Fabišik, Matěj (UMG-J)
Špoutil, František (UMG-J)
Procházka, Jan (UMG-J) ORCID
Kašpárek, Petr (UMG-J)
Pokorná, Jana (UMG-J)
Skopcová, Tereza (UMG-J)
Sedláček, Radislav (UMG-J) RID
Brdička, Tomáš (UMG-J) RIDNumber of authors 11 Article number 1035226 Source Title Frontiers in Immunology. - : Frontiers Media - ISSN 1664-3224
Roč. 13, Dec 20 (2022)Number of pages 12 s. Language eng - English Country CH - Switzerland Keywords neutrophils ; autoinflammation ; chronic multifocal osteomyelitis ; pstpip2 ; PEST-family phosphatases ; ship1 OECD category Immunology R&D Projects GA19-05076S GA ČR - Czech Science Foundation (CSF) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001789 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access UT WOS 000905735100001 DOI 10.3389/fimmu.2022.1035226 Annotation IntroductionAutoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2(cmo). In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1 beta and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1. MethodsTo address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers. ResultsOur data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1 beta production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues. ConclusionsWe demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1 beta pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.frontiersin.org/articles/10.3389/fimmu.2022.1035226/full
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