The underlying mechanisms that drive pathology in infection-induced shock are not well understood. Ixodes ovatus erhlichia (IOE) induces severe inflammation that drives vascular damage, liver injury, and death in C57BL/6 mice. Type I interferons (IFNs) are necessary for IOE-induced shock, though type II IFNs contribute to pathology and mortality. Mice lacking Ifnar, or both Ifnar and Ifngr, have improved survival by 50-70 and 90%, respectively, whereas mice lacking Ifngr alone succumb to disease, similarly to wildtype. Within the bone marrow (BM) neutrophils were reduced suggesting type I IFNs shifted granulocyte production towards eosinophils and basophils. Consistent with these observations, Ifnar and Ifngr signaling was required for chemokines and growth factors (i.e. IL-3, CCL5) associated with eosinophil differentiation and chemotaxis. Within the livers of IOE-infected mice we observed increased eosinophils, and active degranulation was observed in WT, but not in Ifnar-/- and Ifnar-/-; Ifngr-/- mice. Using intravenous labeling we determined that eosinophils are located within the liver parenchyma. The direct effect of type I IFNs on eosinophil activation was evaluated using BM chimeric mice (WT: Ifnar-/- chimeras) where we observed that IFNAR signaling was intrinsically required for enhanced eosinophil activation in the liver. Our data suggest type I IFNs modulate hepatic eosinophil function contributing to hepatic inflammation and exacerbating liver injury.
Type I and II IFNs cooperate with eosinophils to promote liver injury in lethal bacterial infection-induced shock
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Poster and Podium (Block Symposium)
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Date: May 5 Presentation Time: 01:45 PM to 02:00 PM Room: Room W179