AUTHOR=Pavliuchenko Nataliia , Duric Iris , Kralova Jarmila , Fabisik Matej , Spoutil Frantisek , Prochazka Jan , Kasparek Petr , Pokorna Jana , Skopcova Tereza , Sedlacek Radislav , Brdicka Tomas 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1035226

DOI=10.3389/fimmu.2022.1035226

ISSN=1664-3224

ABSTRACT=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 Pstpip2cmo. 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. To address their role in PSTPIP2-mediated control of inflammation, we have generated mouse strains where binding sites for these proteins in PSTPIP2 have been disrupted. Interestingly, mutation of PEST-PTP binding site causes symptomatic disease, while the mice lacking SHIP1 interaction site remain asymptomatic. We found that both PSTPIP2 binding partners equally contribute to the control of IL-1β production, while PEST-PTPs have dominant role in the regulation of reactive oxygen species. Moreover, PEST-PTP interaction with PSTPIP2 was found to regulate another factor accompanying the development of the disease, the increased production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues. Collectively, our data demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 both control IL-1β pathway. Furthermore, PEST-PTPs have additional 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.