Eosinophil migration is regulated by the transcription factor Aiolos

Abstract Accumulation of an abnormally high number of eosinophils (Eos) in tissues often results in damage and organ dysfunction in allergic disease. Preclinical and clinical studies have established that CCR3 ligands (CCL11, CCL24, CCL26) are critical for disease-associated tissue eosinophilia. Yet, blockade of the individual mediators (e.g. CCR3, CCL11) has been insufficient to completely resolve tissue eosinophilia, likely due to simultaneous local expression of multiple Eos-attracting mediators acting in parallel. Thus, delineating the molecular mechanisms that control Eos trafficking into tissues is clinically significant. We recently reported that the transcription factor Aiolos is expressed in murine Eos progenitors (EoPs) as well as mature Eos in mice and humans. We now show that the migratory response of Aiolos-deficient (AiolosKO) Eos is markedly impaired toward CCR3 ligands in vitro and in vivo, along with significantly reduced mRNA and surface expression of CCR3. Notably, migration of AiolosKO Eos toward leukotriene B4 is significantly reduced, suggesting that Aiolos-deficiency results in a global migratory defect. We also demonstrate a profound reduction in Eos accumulation in the small intestine of AiolosKO mice. These latter findings provide in vivo relevance to our findings as intestinal eosinophilia is CCL11 and CCR3 dependent. We further show that migration of adoptively transferred AiolosKO Eos into the airway of allergen-challenged mice was significantly reduced when compared to wild-type Eos in an experimental model of asthma, highlighting an intrinsic defect in tissue trafficking in the AiolosKO Eos. Collectively, our studies implicate Aiolos as a global regulator for eosinophil migration.