CCL26-Targeted siRNA Treatment of Alveolar Type II Cells Decreases Expression of CCR3-Binding Chemokines and Reduces Eosinophil Migration: Implications in Asthma Therapy

Abstract

The underlying infl ammation present in chronic airway diseases is orchestrated by increased expression of CC chemokines that selectively recruit leukocyte populations into the pulmonary system. Human CCL26 signals through CC chemokine receptor 3 (CCR3), is dramatically upregulated in challenged asthmatics, and stimulates recruitment of eosinophils (EOSs) and other leukocytes. CCL26 participates in regulation of its receptor CCR3 and modulates expression of a variety of chemokines in alveolar type II cells. Utilizing the A549 alveolar type II epithelial cell culture model, we carried out studies to test the hypothesis that CCL26-siRNA treatment of these cells would ameliorate Th2-driven release of the eotaxins and other CCR3 ligands that would, in turn, decrease recruitment and activation of EOSs. Results demonstrate that CCL26-siRNA treatments decreased interleukin-4-induced CCL26 and CCL24 expression by > 70%. CCL26-directed small-interfering RNA (siRNA) treatments signifi cantly decreased release of CCL5 (RANTES), CCL15 (MIP-1δ), CCL8 (MCP-2), and CCL13 (MCP-4). In bioactivity assays it was shown that EOS migration and activation were reduced up to 80% and 90%, respectively, when exposed to supernatants of CCL26-siRNA-treated cells. These results provide evidence that CCL26 may be an appropriate target for development of new therapeutic agents designed to alleviate the underlying infl ammation associated with chronic diseases of the airways.

An endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis

“…CCL26 is upregulated in asthmatic patients and recruits eosinophils to inflamed tissues through activation of CCR3 on their surfaces. [109][110][111] TSLP is an alarmin expressed in both the epithelium and endothelium and recruits and activates eosinophils. [112][113][114] TSLP levels correlate with disease severity in asthmatic patients and patients with CRS, 115,116 and treatment of patients with mild asthma with an anti-TSLP antibody reduced their allergic responses and eosinophilia.…”

HMGB1 promotes the secretion of multiple cytokines and potentiates the osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway

“…The CC subfamily, which is also known as the β-chemokine subfamily, is the largest chemokine family, the members of which mainly act on monocytes and lymphocytes (22). In the fracture microenvironment, the secretion of CCL5 and CCL26 by HMGB1-stimulated MSCs may promote the migration of immune cells to tissues affected by the fracture sites, stimulating inflammatory responses and immune reactions (23–25). M-CSF, which is also known as human macrophage-specific colony-stimulating factor (CSF-1), is one of a few cytokines which are directly involved in osteoclastogenesis, osteoclast proliferation and differentiation (26,27).…”

Eosinophil‐derived exosomes contribute to asthma remodelling by activating structural lung cells

“…CCR3 activation is an important pathway that triggers the proliferation process through the MAPK cascade. This receptor can be used by several eotaxins, and even other chemokines such as RANTES, MCP‐2 or MIP‐1δ, which transduces and activates a number of pathways . Thus, the increased BSMC proliferation that we observed when culturing these cells with exosomes from asthmatic patients can occur through CCR3, which induces ERK phosphorylation and generates abnormal proliferation.…”