Migrational guidance of neutrophils is mechanotransduced via high-affinity LFA-1 and calcium flux

Neha Dixit, Itsukyo Yamayoshi, Ari Nazarian, Scott I. Simon

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Acute inflammation triggers the innate immune response of neutrophils that efficiently traffic from the bloodstream to concentrate at high numbers at the site of tissue infection or wounding. A gatekeeper in this process is activation of β2 integrins, which form bond clusters with ICAM-1 on the endothelial surface. These bond clusters serve dual functions of providing adhesive strength to anchor neutrophils under the shear forces of blood flow and directional guidance for cell polarization and subsequent trans-migration on inflamed endothelium. We hypothesized that shear forces transmitted through high-affinity LFA-1 facilitates the cooperation with the calcium release-activated channel Orai1 in directing localized cytoskeletal activation and directed migration. By using vascular mimetic microfluidic channels, we observed neutrophil arrest on a substrate of either ICAM-1 or allosteric Abs that stabilize a high- or low-affinity conformation of LFA-1. Neutrophils captured via low-affinity LFA-1 did not exhibit intracellular calcium flux, F-actin polymerization, cell polarization, or directional migration under shear flow. In contrast, high-affinity LFA-1 provided orientation along a uropod-pseudopod axis that required calcium flux through Orai1. We demonstrate how the shear stress of blood flow can transduce distinct outside-in signals at focal sites of high-affinity LFA-1 that provide contact-mediated guidance for neutrophil emigration.

Original languageEnglish (US)
Pages (from-to)472-481
Number of pages10
JournalJournal of Immunology
Volume187
Issue number1
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Immunology

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