Il-17a Promotes Eosinophil Recruitment From Blood To Lung In Mice With Allergic Lung Disease Triggered By Repetitive Stimulation With Viable Aspergillus Fumigatus

B. J. Murdock , R. A. McDonald , N. R. Falkowski , J. J. Osterholzer , G. B. Toews , G. B. Huffnagle

Author address: 

Univ of Michigan, Ann Arbor, MI, Ann Arbor VA Health System & University of Michigan, Ann Arbor, MI, University of Michigan, Ann Arbor, MI, University of

Abstract: 

Rationale: Persistent intrapulmonary exposure to Aspergillus fumigatus (Af), a ubiquitous airborne fungus, triggers allergic bronchopulmonary aspergillosis (ABPA) in a subset of otherwise healthy individuals. We recently showed that repeated intranasal challenge of immunocompetent mice with viable Af conidia results in an initial regulatory immune response followed by transient tissue eosinophilia and IL-4 production characteristic of a Th2 adaptive immune response. Interestingly, this acute allergic inflammation is accompanied by a sustained increase in IL-17A expression. IL-17A has been implicated in neutrophils (PMN) recruitment in both Th1 and Th17 immune responses. Our objective was to study the role of IL-17A in granulocyte recruitment in our murine model of allergic Th2-type disease. Methods: Wild type (WT; C57BL/6) mice and IL-17A-deficient mice (IL-17-/-; C57BL/6 genetic background) were challenged (intranasally) with 2 million viable Af conidia at weekly intervals. Specific antibody staining and flow cytometric analysis was used to evaluate: a) lung leukocyte subsets (after 0, 2, 4, and 8 Af challenges), b) CD4+ T cell cytokine production (after 0, 2, 4, and 8 Af challenges), c) peripheral blood and bone marrow leukocyte subsets (at 0 and 4 Af challenges), and d) eosinophil expression of CCR3 and IL-5R (at 0 and 4 Af challenges). Results: Accumulation of both PMN and eosinophils was significantly reduced in IL-17-/- mice (relative to WT mice) after 4 Af challenges. Reduced tissue eosinophilia (in IL-17-/- mice) was not associated with changes in IL-4 production by CD4+ T cells or reductions in bone marrow eosinophil precursors. Eosinophils were significantly elevated in the peripheral blood of Af-challenged IL-17-/- mice suggesting a defect in lung trafficking. This defect was not attributable to altered expression of CCR3 or IL-5R which was similar in WT and IL-17-/- mice. Conclusion: These data indicate a novel role for IL-17A in promoting eosinophil recruitment from the blood to the lungs of mice with features of allergic lung disease in response to repetitive stimulation with an airborne fungus. Our results further suggest that IL-17A may be a viable therapeutic target for Th2-mediated disorders such as ABPA or asthma.
2011

abstract No: 

C36

Full conference title: 

American Thoracic Society
    • ATS 2011