In vivo neutralization of α4 and β7 integrins inhibits eosinophil trafficking and prevents lung injury during tropical pulmonary eosinophilia in mice

5 years ago

In vivo neutralization of α4 and β7 integrins inhibits eosinophil trafficking and prevents lung injury during tropical pulmonary eosinophilia in mice

Mrigank Srivastava, Aditi Sharma, Pankaj Sharma

Integrins regulate leukocyte trafficking during homeostasis and inflammatory conditions. However, the role of α4 and β7 integrins in guiding eosinophil transmigration into the lungs during filarial manifestation of Tropical Pulmonary Eosinophilia (TPE) has not been explored. In this study, mice exhibiting TPE manifestations were administered with in vivo neutralizing antibodies against integrins α4 and β7 or their combination and immuno-pathological parameters were evaluated. Results show an intact lung barrier, significantly lower lung inflammation and reduced eosinophil counts in the Bronchoalveolar lavage fluid and lungs of mice receiving anti-α4+β7 treatment. Reduced eosinophil peroxidase and β-hexosaminidase activity, downregulation of inflammatory genes, lower production of inflammatory lipid intermediates like prostaglandins E2 and D2, leukotriene B4 and cysteinyl leukotrienes were also noted in anti-α4+β7 treated mice. Reduced accumulation of central memory, effector memory, regulatory T cells and lower production of IL-4, IL-5, and TGF-β were other cardinal features of anti-α4+β7 treated mice lungs. Flow cytometry-sorted lung eosinophils from anti-α4+β7 treated mice showed higher apoptotic potential, downregulated anti-apoptotic gene Bcl-2, and exhibited reduced F-actin polymerization and calcium influx as compared to IgG controls. In summary, neutralization of α4+β7 integrins impairs the transmigration, activation and survival of eosinophils and reduces TPE induced pathology in mice lungs. Eosinophils are centrally involved in the pathogenesis of filarial manifestation of Tropical Pulmonary Eosinophilia which is caused by entrapment and degeneration of microfilariae in the lung vasculature. Administration of anti-α4+β7 integrin antibodies boosts Th1 immunity, and impairs the transmigration, activation and survival of eosinophils resulting in reduced TPE associated pathology.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/eji.201747086