Neutrophil motility is regulated by both cell intrinsic and endothelial cell ARPC1B

Abstract

Neutrophil directed motility is necessary for host defense, but its dysregulation can also cause collateral tissue damage. Actinopathies are monogenic disorders that affect the actin cytoskeleton and lead to immune dysregulation. Deficiency in ARPC1B, a component of the ARP2/3 complex, results in vascular neutrophilic inflammation; however, the mechanism remains unclear. Here we generated ARPC1B-deficient human iPSC-derived iNeutrophils that show impaired migration and a switch from pseudopodia to the formation of elongated filopodia. We show, using a blood vessel on a chip model, that primary human neutrophils have impaired movement across an endothelium deficient in APRC1B. We also show that the combined deficiency of ARPC1B in iNeutrophils and endothelium results in further reduction in neutrophil migration. Taken together, these results suggest that ARPC1B in endothelium is sufficient to drive neutrophil behavior. Summary statementThe actin regulator ARPC1B in both neutrophils and endothelium drives neutrophil motility.