Abstract
GPI-anchored uPAR is the receptor for the extracellular serine protease urokinase-type plasminogen activator (uPA). Though uPAR role in inflammatory processes is documented, underlying mechanisms are not fully understood. In this study we demonstrate that uPAR is a part of Toll-like receptor 4 (TLR4) interactome. Downregulation of uPAR expression resulted in diminished LPS-induced TLR4 signaling, less activation of NFκB, and decreased secretion of inflammatory mediators in myeloid and non-myeloid cells in vitro. In vivo uPAR−/− mice demonstrated better survival, strongly diminished inflammatory response and better organ functions in cecal ligation and puncture mouse polymicrobial sepsis model. Mechanistically, GPI-uPAR and soluble uPAR colocalized with TLR4 on the cell membrane and interacted with scavenger receptor CD36. Our data show that uPAR can interfere with innate immunity response via TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.
Highlights
UPAR is the receptor for urokinase-type plasminogen activator, an extracellular serine protease and important activator of ubiquitous multifunctional protease plasmin. uPAR is anchored to the outer cell membrane leaflet via GPI anchor
SuPAR promoted LPS response in uPAR−/− cells (Figure 2B) confirming that soluble uPAR (suPAR) can integrate into Toll-like receptor 4 (TLR4) interactome and this integration can have physiological relevance in LPS-induced response
In this study we demonstrated that uPAR promotes TLR4mediated response to LPS in myeloid and non-myeloid cells
Summary
UPAR is the receptor for urokinase-type plasminogen activator (uPA), an extracellular serine protease and important activator of ubiquitous multifunctional protease plasmin. uPAR is anchored to the outer cell membrane leaflet via GPI anchor. UPAR is the receptor for urokinase-type plasminogen activator (uPA), an extracellular serine protease and important activator of ubiquitous multifunctional protease plasmin. UPAR is anchored to the outer cell membrane leaflet via GPI anchor. Binding uPA to uPAR localizes proteolysis at the cell surface to facilitate spatially and temporally restricted activation of plasmin. Binding of uPA or its catalytically inactive amino terminal fragment to uPAR or uPAR overexpression induces intracellular signaling pathways orchestrating important cellular functions such as proliferation, differentiation, migration, DNA repair [1, 3, 4]. Since uPAR is a GPI anchored protein and lacks a transmembrane domain, it relies on interaction with other receptors to transduce signals across cell membrane. UPAR interaction with several transmembrane receptors, integrins, and ECM components has been demonstrated [1] Since uPAR is a GPI anchored protein and lacks a transmembrane domain, it relies on interaction with other receptors to transduce signals across cell membrane. uPAR interaction with several transmembrane receptors, integrins, and ECM components has been demonstrated [1]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
