CCL11 and GM-CSF Differentially Use the Rho GTPase Pathway to Regulate Motility of Human Eosinophils in a Three-Dimensional Microenvironment

Abstract

Asthma is a common disease that causes considerable morbidity. Increased numbers of airway eosinophils are a hallmark of asthma. Mechanisms controlling the entry of eosinophils into asthmatic lung have been intensively investigated, but factors regulating migration within the tissue microenvironment are less well understood. We modeled this by studying chemoattractant and growth factor-mediated human eosinophil migration within a three-dimensional collagen matrix. Stimulation with GM-CSF induced dose-dependent, random migration with a maximum of 77 ± 4.7% of cells migrating. In contrast, CCL11 and C5a caused a more modest although significant degree of migration (19 ± 1.8% and 20 ± 2.6%, respectively). Migration to GM-CSF was partially dependent on Ca2+ and αΜβ2 integrins. The Rho family of small GTPases regulates intracellular signaling of cell migration. GM-CSF-induced migration was only partially dependent on Rho kinase/Rho-associated kinase (ROCK) and was independent of RhoA activation. In contrast, CCL11-induced migration was fully dependent on both RhoA and ROCK. Activation of RhoA was therefore neither necessary nor sufficient to cause eosinophil migration in a three-dimensional collagen environment. This study suggests that eosinophil growth factors are likely to be required for eosinophil migration within the bronchial mucosa, and this involves signal transduction pathways distinct from those used by G protein-associated chemoattractants.

Simvastatin Inhibits Airway Hyperreactivity

“…Simvastatin can induce eosinophilic apoptosis in an MA-dependent fashion (29), while Ras regulates eosinophil chemotaxis and survival (30). Furthermore, the observed simvastatin inhibition of airway eosinophilia ( Figure 1B) could also be due to broader systemic effects on T cells with subsequent inhibition of eosinophilic chemotaxis and transmigration (31,32). Statins also modulate monocyte-macrophage function and inflammatory responses (33,34), consistent with our finding of reduced BALF macrophage counts ( Figure 1D).…”

Control of Homeostasis and Dendritic Cell Survival by the GTPase RhoA

“…Therefore, further work is necessary to differentiate whether apoptosis of RhoA-ko DCs is caused by defective mitosis, direct regulation of PI3K by RhoA, or both. However, there is indirect evidence from the literature that receptors for DC growth factors GM-CSF (20,21) and Flt3L (22) can signal via RhoA. In cells bearing the oncogenic form of Flt3, a signaling pathway via PI3K is activated (22).…”

“…It also contributes to maintenance of homeostatic DC numbers by regulating proliferation (19). GM-CSF signals involve RhoA GTPase pathways in various cell types (20,21). Also, signaling via mutated Flt3 in acute myeloid leukemia exploits a pathway involving RhoA for survival and proliferation of tumor cells (22).…”

Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis

“…68 Eotaxin possesses selective chemotactic activity for eosinophils. 69,70 Chemokines not only induce chemotaxis, but also activate these target cells in the bladder, and thereby contribute to the inflammatory-induced changes in BPS/IC.…”