Ceramide-1-Phosphate: a new player in modulating DC in allergic airway inflammation!?
Final Report Abstract
Allergic asthma is one of the most common chronic diseases in Western societies. Clinically it is characterized by variable airway obstruction, excessive mucus production and hyperresponsiveness to non-specific stimulus [www.ginaasthma.com]. Thereby the non-resolved chronic inflammation is orchestrated by eosinophils, mast cells, Th2 lymphocytes and dendritic cells (DCs), resulting in airway remodeling (1), which is closely associated with the degree of airway obstruction and hyper-responsiveness (2). Dendritic cells have been shown to be essential in the induction and maintenance of T helper 2 (TH2)-cell responses to inhaled allergens in asthma. Recent studies suggest that sphingolipid mediators (like ceramide, ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P)) are involved in regulating inflammation, via intracellular signalling pathway and/or binding to specific plasma-membrane receptors. While the role of S1P in the pathogenesis of asthma and DC biology has been extensively studied, little is know about C1P. Preliminary data by our group revealed that C1P might exert anti-inflammatory effects in acute allergic airway inflammation via modulation DC function. In the present study we wanted to investigate whether: 1) C1P can inhibit all cardinal features of acute and chronic experimental asthma; 2) C1P modulates the maturation, cytokine production and T cell priming capacity of bone marrow derived DC in vitro and in vivo 3) C1P effects the migration and TH2-priming of endogenous DC in vivo; 4) C1P influences maturation, cytokine production and T cell priming of human monocyte derived DC-function. 5) Does C1P interact with ORMDL-expression? 1) Complex experiments in our different mouse models of allergic airway inflammation enlighten that intrapulmonary application of C1P decreases all cardinal features of allergic airway inflammation (AAI). 2) Mechanistically we show that C1P can modulate critical functions of human and mouse dendritic cells leading to reduce Th2-inflammation in the mouse models of AAI. In summary our data suggest that application of C1P by targeting lung DC function might be a new therapeutic option for the treatment of severe asthma. Of note within this funded project on the role of C1P in asthma pathology, we extended this project by also investigating the effect of C1P in LPS- and cigarette smoke induced lung inflammation. Strikenly as mentioned above C1P was also able to reduce LPS-induced ARDS and CS-induced lung inflammation/emphysema by regulating key inflammatory cell responses (such as NFkappa-B signaling) in leucocytes.
