A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma

Abstract

Background Sphingosine-1-phosphate (S1P) produced by two sphingosine kinase isoenzymes, SphK1 and SphK2, has been implicated in IgE-mediated mast cell responses. However, studies of allergic inflammation in isotype-specific SphK knockout mice have not clarified their contribution and the role that S1P plays in vivo in a mast cell and IgE-dependent mouse model of allergic asthma has not yet been examined. Objective We used an isoenzyme-specific SphK1 inhibitor, SK1-I, to investigate the contributions of S1P and SphK1 to mast cell dependent airway hyperresponsiveness (AHR) and airway inflammation in mice. Methods Allergic airway inflammation and AHR were examined in a mast cell-dependent mouse model of ovalbumin (OVA)-induced asthma. C57BL/6 mice received intranasal delivery of SK1-I prior to sensitization and challenge with OVA or only prior to challenge. Results SK1-I inhibited antigen-dependent activation of human and murine mast cells and suppressed activation of NF-κB, a master transcription factor that regulates expression of pro-inflammatory cytokines. SK1-I treatment of mice sensitized to OVA in the absence of adjuvant, which develop mast cell-dependent allergic inflammation, significantly reduced OVA-induced AHR to methacholine; decreased numbers of eosinophils and levels of the cytokines IL-4, 5, 6, 13, IFN-γ, and TNF-α and the chemokines eotaxin, and CCL2 in bronchoalveolar lavage fluid; and decreased pulmonary inflammation as well as activation of NF-κB in the lungs. CONCLUSION S1P and SphK1 play important roles in mast cell-dependent, OVA-induced allergic inflammation and AHR, in part by regulating the NF-κB pathway.

Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance

“…Our findings that adipocyte and macrophage inflammatory responses are reduced in HFD-fed SK1 Ϫ/Ϫ mice complement a growing body of literature implicating SK1/S1P signaling in inflammation, immune cell function, and disease (25,41). The SK1-S1P axis contributes to Toll-like receptor 4 signaling (31, 41) and promotes activation of IKK and NF-B (33,41), responses that can directly inhibit insulin signaling (29). Our observation that ATM accumulation is reduced in DIO SK1 Ϫ/Ϫ mice is consistent with decreased levels of MCP-1 in SK1 Ϫ/Ϫ mice and established roles of SK1/S1P in trafficking and migration of numerous immune cells, including macrophages (13).…”

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

“…An understanding of the involvement of sphingolipids in the asthmatic phenotype is under development. The potent signaling lipid sphingosine-1-phosphate stimulates histamine release from mast cells ( 21 ) and an inhibitor of sphingosine kinase, which generates sphingosine-1-phosphate, reduces airway hypersensitivity in a murine asthma model ( 22 ). The sensitivity induced by elevated sphingosine-1-phosphate does not easily fi t with the increased hypersensitivity induced by SPT inhibition ( 18 ) and the reduced sphingolipid levels noted in these studies presented here.…”

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

“…It is known from the literature that a deficiency of both sphingosine kinases, leads to embryonic lethality. However, no obvious phenotype is known in single knockout mice, indicating that apart from specific exceptions (Oskeritzian et al, 2008;Price et al, 2013) one enzyme may substitute the other (Alemany et al, 2007). The increased concentration of FTY720-P in the cytosol of the SphK1-deficient cells may thus be the result of a compensatory increase of SphK2 activity.…”