Sneezing, wheezing and other unpleasant symptoms of asthma and allergic responses result from factors released by activated eosinophils - very short-lived blood cells that are rapidly recruited to body sites, such as the lung and skin, upon contact with allergens.
Coincident with this tissue infiltration, eosinophils become activated and release multiple inflammatory mediators, including GM-CSF, a survival factor that increases the lifespan of eosinophils. In the December issue of Nature Immunology, researchers identify the enzyme Pin1 that increases the stability of mRNAs encoding GM-CSF. Targeting Pin1 activity may therefore reduce or alleviate many allergic reactions.
Key to controlling allergic reactions is to understand how eosinophil longevity is increased upon their recruitment to allergen-sensitized tissues. James Malter and colleagues show Pin1 regulates GM-CSF mRNA abundance by altering its binding to one of two factors, AUF1 or hnRNP C, leading to rapid GM-CSF mRNA destruction or increased stability, respectively. Pin1 alters AUF1 to prevent its binding to GM-CSF mRNA, which then bind to hnRNP C instead. This step leads to increased GM-CSF protein synthesis, in turn leading to increased eosinophil survival. Importantly, Pin1 is activated by signals the eosinophil receives after exiting the bloodstream, ensuring eosinophil survival in the affected tissue sites.
To show the potential clinical relevance of these findings, the authors collected eosinophils from the lungs of human volunteers who had been challenged with aerosolized allergens. Eosinophils isolated after such challenge show increased Pin1 activity (and longer survival times) as compared to blood-borne eosinophils isolated from these same individuals. Culturing the lung eosinophils with Pin1 inhibitors reduces eosinophil survival. These results show Pin1 plays a crucial role in determining how long eosinophils will live. These findings point to potential therapeutic strategies to target Pin1 activity in allergy patients, lessening their unpleasant immune response to allergen exposure.
James S. Malter (University of Wisconsin School of Medicine, Madison, WI, USA)
Abstract available online: Malter Paper.
(C) Nature Immunology press release.
Message posted by: Trevor M. D'Souza