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Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation

INTRODUCTION: Autoinflammatory 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...

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Autores principales: Pavliuchenko, Nataliia, Duric, Iris, Kralova, Jarmila, Fabisik, Matej, Spoutil, Frantisek, Prochazka, Jan, Kasparek, Petr, Pokorna, Jana, Skopcova, Tereza, Sedlacek, Radislav, Brdicka, Tomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807597/
https://www.ncbi.nlm.nih.gov/pubmed/36605205
http://dx.doi.org/10.3389/fimmu.2022.1035226
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author Pavliuchenko, Nataliia
Duric, Iris
Kralova, Jarmila
Fabisik, Matej
Spoutil, Frantisek
Prochazka, Jan
Kasparek, Petr
Pokorna, Jana
Skopcova, Tereza
Sedlacek, Radislav
Brdicka, Tomas
author_facet Pavliuchenko, Nataliia
Duric, Iris
Kralova, Jarmila
Fabisik, Matej
Spoutil, Frantisek
Prochazka, Jan
Kasparek, Petr
Pokorna, Jana
Skopcova, Tereza
Sedlacek, Radislav
Brdicka, Tomas
author_sort Pavliuchenko, Nataliia
collection PubMed
description INTRODUCTION: Autoinflammatory 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-1β 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. METHODS: To 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. RESULTS: Our 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-1β 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. CONCLUSIONS: We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β 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.
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spelling pubmed-98075972023-01-04 Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation Pavliuchenko, Nataliia Duric, Iris Kralova, Jarmila Fabisik, Matej Spoutil, Frantisek Prochazka, Jan Kasparek, Petr Pokorna, Jana Skopcova, Tereza Sedlacek, Radislav Brdicka, Tomas Front Immunol Immunology INTRODUCTION: Autoinflammatory 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-1β 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. METHODS: To 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. RESULTS: Our 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-1β 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. CONCLUSIONS: We demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β 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. Frontiers Media S.A. 2022-12-20 /pmc/articles/PMC9807597/ /pubmed/36605205 http://dx.doi.org/10.3389/fimmu.2022.1035226 Text en Copyright © 2022 Pavliuchenko, Duric, Kralova, Fabisik, Spoutil, Prochazka, Kasparek, Pokorna, Skopcova, Sedlacek and Brdicka https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pavliuchenko, Nataliia
Duric, Iris
Kralova, Jarmila
Fabisik, Matej
Spoutil, Frantisek
Prochazka, Jan
Kasparek, Petr
Pokorna, Jana
Skopcova, Tereza
Sedlacek, Radislav
Brdicka, Tomas
Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title_full Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title_fullStr Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title_full_unstemmed Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title_short Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation
title_sort molecular interactions of adaptor protein pstpip2 control neutrophil-mediated responses leading to autoinflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807597/
https://www.ncbi.nlm.nih.gov/pubmed/36605205
http://dx.doi.org/10.3389/fimmu.2022.1035226
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