Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate

Abstract

Sphingosine 1-phosphate (S1P) is a sphingolipid mediator that is involved in diverse biological functions. Local administration of S1P causes inflammation coupled to a large eosinophil (EO) recruitment in the rat-paw tissue. The inflammatory response is accompanied by an increase in S1P receptors, namely S1P 1, S1P2, S1P3, and by an enhanced expression of CCR3, which is the main chemokine receptor known to be involved in EO function. Human EOs constitutively express S1P 1 and, at a lower extent, S1P2, S1P3 receptors. S1P in vitro causes cultured human EO migration and an increase in S1P receptor mRNA copies and strongly up-regulates CCR3 and RANTES (regulated on activation, normal T cell-expressed and secreted) message levels; in particular CCR3 is up-regulated 18,000-fold by S1P. A blocking anti-CCR3 Ab inhibits S1P-induced chemotaxis, implying that S1P acts as specific recruiting signal for EOs not only through its own receptors but also through CCR3. These results show that S1P is involved in EO chemotaxis and contribute to shed light on the complex mechanisms underlying EO recruitment in several diseases such as asthma and some malignancies.

The Sphingosine 1-Phosphate Receptor, S1PR1, Plays a Prominent But Not Exclusive Role in Enhancing the Excitability of Sensory Neurons

“…The idea that peripheral S1P can be proinflammatory is supported by the observation that injection of S1P into the paw of a rat produced a dose-dependent edema that was associated with a significant infiltration of eosinophils (Roviezzo et al 2004). Synovial tissue isolated from patients with rheumatoid arthritis exhibited increased expression S1PR 1 compared with those with osteoarthritis.…”

SKI-II, an Inhibitor of Sphingosine Kinase, Ameliorates Antigen-Induced Bronchial Smooth Muscle Hyperresponsiveness, but Not Airway Inflammation, in Mice

“…Ammit and colleagues (9) firstly demonstrated that S1P levels are elevated in the airways of individuals with asthma after segmental allergen challenge. The finding that S1P can act as a chemotactic agent for eosinophils further suggests an involvement of S1P in pathophysiology of asthma (10). Indeed, inhalation of inhibitors for sphingosine kinase, which produces S1P directly from sphingosine, attenuated antigen-induced airway inflammation in mice (11).…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…The mechanisms by which S1P modulate the pathogenesis of inflammation are ill defined but S1P acts via five specific receptors, S1P 1À5 (Chun et al, 2002). S1P can activate monocytes, endothelial cells, mast cells, eosinophils, smooth muscle cells and promote tissue recruitment of leukocytes (Roviezzo et al, 2004). Studies reveal an involvement for S1P in asthma, RA, IBD and atherosclerosis (Ammit et al, 2001;Kitano et al, 2006;Daniel et al, 2007;Nofer et al, 2007).…”