CXCL5 Regulates Chemokine Scavenging and Pulmonary Host Defense to Bacterial Infection

Abstract

Summary The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation.

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

“…Following this treatment, the bone marrow cells of the left tibia (tumorinoculated) and the contralateral right tibia (control) were iso-(Supplemental Figure 5A). These findings agree with the previously reported increase in Gr-1 + cells in CXCL5 -/-mice and the suggested role of this cytokine in bone marrow neutrophil homeostasis (38). Increased numbers of neutrophils were also found in the blood of CXCL5 -/-mice relative to WT, but no changes in other leukocytes were observed (Supplemental Figure 5B).…”

“…In these experiments tumor growth jci. In mice, CXCL5 exhibits a predominant role in the neutrophil influx to the lung as a result of inflammation induced by LPS inhalation, which aligns with its role in human inflammatory diseases as a neutrophil chemoattractant (38). The expression of CXCL6, a human homolog of mouse CXCL5 (60), was significantly upregulated in prostate cancer tissues and correlated with high Gleason scores (≥7) (61).…”

“…-/-knockout mice on a C57BL/6J background were donated by George Scott Worthen and Junjie Mei (Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA) (38). Vossicle (vertebral body) subcutaneous RM1-iC9 tumors.…”

CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis

“…CXCL15, which is produced by bronchial epithelial cells (29), contributes to pulmonary defense against K. pneumoniae infection (37). CXCL5, which plays a role in LPS-induced lung inflammation, is secreted by type I and type II alveolar epithelial cells (AECI and AECII, respectively) (31,(38)(39)(40)(41). During M. tuberculosis infection, CXCR2 and its ligand CXCL5 are strongly upregulated in lungs (9,42,43).…”

Differential Regulation of CXCL5 by FGF2 in Osteoblastic and Endothelial Niche Cells Supports Hematopoietic Stem Cell Migration

“…CXCL5 is associated with neutrophile influx into inflamed tissues [25,52] and with neutrophile homeostasis. This chemokine also has a proliferative effect on HSC maintenance [27].…”