Journal Article

The CXCL12/CXCR4 Signaling Axis Retains Neutrophils at Inflammatory Sites in Zebrafish

Herman, Kimberly D., Prince, Lynne R., Renshaw, Stephen A., Elks, Philip M., Robertson, Anne L., Loynes, Catherine A., Isles, Hannah M.

2019

Overview

The inappropriate retention of neutrophils at inflammatory sites is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS, and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well-studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signaling axis in modulating neutrophil retention at inflammatory sites. We used an tissue injury model to study neutrophilic inflammation using transgenic zebrafish larvae. Expression of and during the tissue damage response was assessed using hybridization and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown and in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signaling axis pharmacologically. We identified that and are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in and CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signaling axis accelerated resolution of the neutrophil component of inflammation, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signaling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Apoptosis / Cell Movement - genetics / Cell Movement - immunology / chemokine / Chemokine CXCL12 - genetics / Chemokine CXCL12 - immunology / Chemokines / Chronic obstructive pulmonary disease / CRISPR / CXCL12 / CXCL12 protein / CXCR4 / CXCR4 protein / Cystic fibrosis / Danio rerio / Embryos / Gene expression / Gene Knockdown Techniques / Hybridization / Immunology / Inflammation / Inflammation - genetics / Inflammation - immunology / Inflammation - pathology / Inflammatory diseases / Larvae / Leukocyte migration / Leukocytes (neutrophilic) / Mutation / neutrophil / Neutrophils / Neutrophils - immunology / Neutrophils - pathology / Proteins / Receptors, CXCR4 - genetics / Receptors, CXCR4 - immunology / Retention / Rheumatoid arthritis / Signal Transduction - genetics / Signal Transduction - immunology / Zebrafish - genetics / Zebrafish - immunology / Zebrafish Proteins - genetics / Zebrafish Proteins - immunology