Differential attenuation of β2 integrin–dependent and –independent neutrophil migration by Ly6G ligation

Abstract

Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on β2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of β2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)–mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of β2 integrin dependence in neutrophil migration.

Neutrophil Heterogeneity as Therapeutic Opportunity in Immune-Mediated Disease

“…Resulting enhancement in integrin expression and affinity translate CD177 ligation into neutrophil arrest, blocking transmigration (89). CD177 thus functionally echoes murine Ly6G, a neutrophil-restricted GPI-linked protein from the same Ly6/UPAR protein family that also interacts with β2 integrins and can modulate neutrophil migration, although Ly6G ligation appears to impair rather than enhance integrin binding (15, 90, 91). The endogenous receptor for CD177 remains uncertain.…”

“…Neutrophils lacking all integrins can migrate through the 3-dimensional matrix of tissue interstitium via amoeboid motion (“flowing and squeezing”) (114) Mice lacking β2 integrins or subject to integrin blockade still mount neutrophilic infiltrates. In particular, neutrophils can enter the airway without β2 integrins, although entry into the pulmonary parenchyma exhibits partial integrin dependence, as shown in studies employing adoptive transfer of mixed wild-type and CD18–/– neutrophils (90, 115–120) Indeed, under certain circumstances integrins slow neutrophil migration into lung, such that impairing integrins actually promotes neutrophil entry (116, 120). Consistent with these murine findings, neutrophilic pneumonia is observed in humans and cows lacking CD18, although recurrent pulmonary infections remain a clinical feature of this immunodeficiency in both species (113, 121, 122).…”

“…Consistent with these murine findings, neutrophilic pneumonia is observed in humans and cows lacking CD18, although recurrent pulmonary infections remain a clinical feature of this immunodeficiency in both species (113, 121, 122). In peritoneum, migratory impairment resulting from integrin deficiency or blockade is partial, with marked variability among experimental systems (90, 115, 116, 123–125). In the liver, integrins mediate neutrophil accumulation after thermal injury but are dispensable for migration induced by live bacteria in favor of CD44-hyaluronan adhesion (126).…”

“…Co-transfer of WT and CD18–/– neutrophils identified a markedly greater role for β2 integrins in sterile than septic peritonitis (i.p. IL-1β vs. live E. coli ) (90). Correspondingly, targeting integrin-mediated neutrophil recruitment via an antibody directed against the integrin modulator Ly6G attenuated only sterile neutrophil infiltration, and then only in neutrophils expressing CD18.…”

Kidney injury enhances renal G-CSF expression and modulates granulopoiesis and human neutrophil CD177 in vivo

“…While understanding of the clinical impact of baseline and induced human neutrophil subsets progresses , the fact that the dichotomous human neutrophil CD177 phenotype and the mechanisms of human CD177 interaction with proteinase 3 and integrins do not apply to its murine homologue have impaired functional studies of this specific subtype . Very recent data on a differential role in migration depending on the underlying stimulus for murine Ly6G , a protein of similar structure as CD177, should be considered when planning prospective human studies with parallel assessment of systemic and local CD177 phenotypes in inflammation. Renal transplant recipients may be considered for such a study, as the kidney graft is frequently biopsied and different forms of inflammation are observed.…”