Benjamin Lenz (Bonn / DE), Dr. rer. nat. Alexandra Ehrens (Bonn / DE), Josephine Gal (Paris / FR), Dr. Jesuthas Ajendra (Bonn / DE), Frederic Risch (Bonn / DE), Dr. Henry McSorley (Dundee / GB), Prof. Dr. Coralie Martin (Paris / FR), Achim Hoerauf (Bonn / DE), Prof. Dr. Marc P. Hübner (Bonn / DE)
Abstract text
Background: Eosinophilia is a hallmark of helminth infection and eosinophils are essentially involved in the protective immune responses against helminths. The distinct role of eosinophils during parasitic filarial infection, allergy and autoimmune disease-derived pathology is still not sufficiently understood. In this study, we established a mouse model for tropical pulmonary eosinophilia (TPE), a clinical manifestation that is caused by eosinophil hyper-responsiveness within the lung of lymphatic filariasis patients to investigate involved mechanisms.
Methods: Wild-type (WT) BALB/c mice were sensitized with dead microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis in weekly intervals for a total of three times and subsequently challenged with viable microfilariae (MF) to induce TPE. The resulting immune response was compared to non-sensitized wild-type mice as well as sensitized eosinophil-deficient dblGATA mice using flow cytometry, lung histology and ELISA. Further, the role of IL-33 signaling during TPE development was investigated using the IL-33 signaling blocker HpARI.
Results: Sensitized WT mice displayed increased eosinophil numbers in blood, BAL, spleen and lung. The eosinophilia was accompanied with enhanced MF clearance from the blood, increased immune cell numbers in the lung, increased IL-33 serum levels and activation of lung eosinophils in TPE-induced WT mice in comparison to non-sensitized WT mice and dblGATA TPE mice. Further, TPE-induced WT mice had an increased number of group 2 innate lymphoid cells (ILC2) and alternatively activated macrophages (AAM) within the lung when compared to non-sensitized WT mice. Lung retention of MF was drastically increased in sensitized mice. Interestingly, blocking of IL-33 signaling prevented a type–2 immune shift, reducing M2 macrophages, lung ILC2s and eosinophils.
Conclusion: Repeated sensitization with L. sigmodontis MF induces pulmonary eosinophilia accompanied with a strong type 2 immune response mimicking human TPE. Using this newly established L. sigmodontis TPE mouse model, we demonstrate that IL-33 is a key alarmin, which is essentially involved in the induction of TPE-associated immune responses.