PLCε1 regulates SDF-1α-induced lymphocyte adhesion and migration to sites of inflammation

Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2693-2698. doi: 10.1073/pnas.1612900114. Epub 2017 Feb 17.

Abstract

Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCε1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCε1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCε1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCε1, suggesting that PLCε1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

Keywords: PLCε1; Rap1; SDF-1α; T cells; adhesion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / genetics
  • Cell Adhesion / immunology
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Chemokine CXCL12 / genetics*
  • Chemokine CXCL12 / immunology
  • Humans
  • Inflammation / genetics*
  • Inflammation / immunology
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / immunology
  • Lymphocytes / immunology
  • Lymphocytes / pathology
  • Mice
  • Phosphoinositide Phospholipase C / genetics*
  • Phosphoinositide Phospholipase C / immunology
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Telomere-Binding Proteins / genetics*
  • Telomere-Binding Proteins / immunology
  • ras-GRF1 / immunology

Substances

  • Chemokine CXCL12
  • Receptors, Antigen
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • ras-GRF1
  • Intercellular Adhesion Molecule-1
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon