TY - JOUR
T1 - Defective Neutrophil Transendothelial Migration and Lateral Motility in ARPC1B Deficiency Under Flow Conditions
AU - Kempers, Lanette
AU - Sprenkeler, Evelien G. G.
AU - van Steen, Abraham C. I.
AU - van Buul, Jaap D.
AU - Kuijpers, Taco W.
N1 - Funding Information: ES and TK are supported by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 668303 and TK is supported by the E-Rare ZonMW grant #90030376506. AS is supported by LSBR grant #1649. LK is supported by LSBR grant #1820 JB is supported by ZonMW NWO Vici grant # 91819632. Publisher Copyright: © Copyright © 2021 Kempers, Sprenkeler, van Steen, van Buul and Kuijpers. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/31
Y1 - 2021/5/31
N2 - The actin-related protein (ARP) 2/3 complex, essential for organizing and nucleating branched actin filaments, is required for several cellular immune processes, including cell migration and granule exocytosis. Recently, genetic defects in ARPC1B, a subunit of this complex, were reported. Mutations in ARPC1B result in defective ARP2/3-dependent actin filament branching, leading to a combined immunodeficiency with severe inflammation. In vitro, neutrophils of these patients showed defects in actin polymerization and chemotaxis, whereas adhesion was not altered under static conditions. Here we show that under physiological flow conditions human ARPC1B-deficient neutrophils were able to transmigrate through TNF-α-pre-activated endothelial cells with a decreased efficiency and, once transmigrated, showed definite impairment in subendothelial crawling. Furthermore, severe locomotion and migration defects were observed in a 3D collagen matrix and a perfusable vessel-on-a-chip model. These data illustrate that neutrophils employ ARP2/3-independent steps of adhesion strengthening for transmigration but rely on ARP2/3-dependent modes of migration in a more complex multidimensional environment.
AB - The actin-related protein (ARP) 2/3 complex, essential for organizing and nucleating branched actin filaments, is required for several cellular immune processes, including cell migration and granule exocytosis. Recently, genetic defects in ARPC1B, a subunit of this complex, were reported. Mutations in ARPC1B result in defective ARP2/3-dependent actin filament branching, leading to a combined immunodeficiency with severe inflammation. In vitro, neutrophils of these patients showed defects in actin polymerization and chemotaxis, whereas adhesion was not altered under static conditions. Here we show that under physiological flow conditions human ARPC1B-deficient neutrophils were able to transmigrate through TNF-α-pre-activated endothelial cells with a decreased efficiency and, once transmigrated, showed definite impairment in subendothelial crawling. Furthermore, severe locomotion and migration defects were observed in a 3D collagen matrix and a perfusable vessel-on-a-chip model. These data illustrate that neutrophils employ ARP2/3-independent steps of adhesion strengthening for transmigration but rely on ARP2/3-dependent modes of migration in a more complex multidimensional environment.
KW - ARP2/3 complex
KW - ARPC1B deficiency
KW - inborn error of immunity
KW - neutrophil
KW - neutrophil transmigration
KW - primary immunodeficiency
KW - vessel-on-a-chip
UR - http://www.scopus.com/inward/record.url?scp=85107854738&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2021.678030
DO - https://doi.org/10.3389/fimmu.2021.678030
M3 - Article
C2 - 34135903
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 678030
ER -