Mice genetically inactivated in interleukin‐17A receptor are defective in long‐term control of Mycobacterium tuberculosis infection

D Freches, H Korf, O Denis, X Havaux, K Huygen… - …, 2013 - Wiley Online Library
D Freches, H Korf, O Denis, X Havaux, K Huygen, M Romano
Immunology, 2013Wiley Online Library
Summary Interleukin‐17A (IL‐17A), a pro‐inflammatory cytokine acting on neutrophil
recruitment, is known to play an important role during M ycobacterium tuberculosis infection,
but the role of IL‐17 A receptor signalling in immune defence against this intracellular
pathogen remains poorly documented. Here we have analysed this signalling using C 57
BL/6 mice genetically inactivated in the IL‐17 receptor A subunit (IL‐17 RA−/−). Although
early after infection bacterial growth was controlled to the same extent as in wild‐type mice …
Summary
Interleukin‐17A (IL‐17A), a pro‐inflammatory cytokine acting on neutrophil recruitment, is known to play an important role during Mycobacterium tuberculosis infection, but the role of IL‐17A receptor signalling in immune defence against this intracellular pathogen remains poorly documented. Here we have analysed this signalling using C57BL/6 mice genetically inactivated in the IL‐17 receptor A subunit (IL‐17RA−/−). Although early after infection bacterial growth was controlled to the same extent as in wild‐type mice, IL‐17RA−/− mice were defective in exerting long‐term control of M. tuberculosis infection, as demonstrated by a progressively increasing pulmonary bacterial burden and shortened survival time. Compared with infected wild‐type mice, IL‐17RA−/− mice showed impaired recruitment of neutrophils to the lungs at the early but not the late stage of infection. Pulmonary tumour necrosis factor‐α, IL‐6 and particularly IL‐10 levels were decreased in the absence of IL‐17RA signalling, whereas IL‐1β was increased. CD4+‐mediated and γδ‐mediated IL‐17A production was dramatically increased in IL‐17RA−/− mice (confirming part of their phenotype), whereas production of interferon‐γ and expression of the bactericidal enzyme inducible nitric oxide synthase were not affected. Collectively, our data suggest that early but not late neutrophil recruitment is essential for IL‐17A‐mediated long‐term control of M. tuberculosis infection and that a functional interferon‐γ response is not sufficient to control M. tuberculosis growth when the IL‐17RA pathway is deficient. As treatment of auto‐immune diseases with anti‐IL‐17A antibodies is actually being tested in clinical studies, our data suggest that caution should be taken with respect to possible reactivation of tuberculosis.
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