Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma

The pathophysiology of allergic asthma is driven by T-helper 2 (Th2) immune responses following aeroallergen inhalation. The mechanisms that initiate, potentiate and regulate airways allergy are incompletely characterized. We have previously shown that Hedgehog (Hh) signaling to T-cells, via downstream Gli transcription factors, enhances T-cell conversion to a Th2 phenotype. Here, we show for the first time that Gli-dependent transcription is activated in T-cells in vivo during murine allergic airways disease (AAD) a model for the immunopathology of asthma; and that genetic repression of Gli signaling in Tcells decreases the differentiation and/or recruitment of Th2 cells to the lung. We report that T-cells are not the only cells capable of expressing activated Gli during AAD. A substantial proportion of eosinophils and lung epithelial cells, both central mediators of the immunopathology of asthma, are also able to undergo Hh/Gli signaling. Finally, we show that Shh increases Il4 expression in eosinophils. We therefore propose that Hh signaling during AAD is complex, involving multiple cell types, signaling in an auto- or paracrine fashion. Improved understanding of the role of this major morphogenetic pathway in asthma may give rise to new drug targets for this chronic condition

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation