The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury

Abstract

Inflammatory stimuli, such as a microbes or lipopolysaccharides, induce a rapid release of neutrophils from the bone marrow and promote neutrophil migration into inflamed sites to promote host defense. However, an excess accumulation and retention of neutrophils in inflamed tissue can cause severe tissue injuries in the later stages of inflammation. Recent studies have reported that both CXCL12 levels in injured lungs and its receptor, CXCR4, on accumulated neutrophils in injured lungs, increased; furthermore, these studies showed that the CXCL12/CXCR4 signaling pathway participated in neutrophil accumulation in the later stages of lipopolysaccharide (LPS)-induced lung injury. However, the mechanisms underlying this increase in surface CXCR4 expression in neutrophils remain unclear. In this study, we found that surface CXCR4 expression increased in extravascular, but not intravascular, neutrophils in the lungs of LPS-induced lung injury model mice. Furthermore, ex vivo studies revealed that CXCL12 acted not only as a chemoattractant, but also as a suppressor of cell death for the lung neutrophils expressing CXCR4. Sulfatide, one of the native ligands for L-selectin, induced the increase of surface CXCR4 expression on isolated circulating neutrophils, suggesting that the activation of L-selectin may be involved in the increase in surface CXCR4. Our findings show that surface CXCR4 levels on neutrophils increase after extravasation into injured lungs, possibly through the activation of L-selectin. The CXCL12/CXCR4 signaling pathway plays an important role in the modulation of neutrophil activity during acute lung injury, not only by promoting chemotaxis but also by suppressing cell death.

Migrating Myeloid Cells Sense Temporal Dynamics of Chemoattractant Concentrations

“…In addition to their well-established spatial sensing capabilities, neutrophils and immature DC thus can read the temporal evolution of chemokine concentrations, a capacity that may be intimately linked to determining whether an infection is increasing or resolving and limiting effector cell recruitment capable of added tissue damage in the latter case. Indeed, both CCL19 and CXCL12 have been found to regulate neutrophil and dendritic cell recruitment under conditions involving responses to acute stimuli, as opposed to organismal steady states (Delano et al, 2011; Robbiani et al, 2000; Yamada et al, 2011), conditions where the cells’ ability to adjust their migratory responses to the temporal evolution of the chemotactic signal may play a central role in preventing immunopathology.…”

The mercurial nature of neutrophils: still an enigma in ARDS?

“…Disruption of these heteromers attenuated experimental sepsis and LPS-induced lung injury. LPStreated mice also have elevated levels of the related chemokine CXCL12 and increased migration of CXCR4ϩ neutrophils (185). Moreover, CXCL12 was shown to reduce neutrophil apoptosis in inflamed lungs.…”

The Pivotal Role of CXCR7 in Stabilization of the Pulmonary Epithelial Barrier in Acute Pulmonary Inflammation

“…In terms of acute pulmonary inflammation, PMNs migrating into the lung showed increased CXCR4 levels (10), and SDF-1 protein expression in pulmonary tissue rose (7). Blocking SDF-1 showed anti-inflammatory effects with reduced PMN migration into the alveolar space (7).…”

“…The focus of previous studies on SDF-1 in acute pulmonary inflammation was based on the chemokine itself or on CXCR4 (7,10). We therefore chose to investigate the detailed role of CXCR7 in acute pulmonary inflammation and evaluated its effects on lung tissue and PMNs, chemokine release, and alveolo-capillary barrier function.…”