IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense.
The role of interleukin-17A (IL-17A) in host defense against Legionella pneumophila remains elusive. To address this issue, we used Il17a(-/-), Il17f(-/-), and Il17a/Il17f(-/-) mice on a C57Bl/6 (non-permissive) background and IL-17 neutralizing Abs in mice on an A/J (permissive) background. Higher bacterial (L. pneumophila) counts in the lung and blood along with reduced neutrophil recruitment were detected in Il17a(-/-), but not Il17f(-/-), mice. We found that neutrophils produce IL-17A homodimer (IL-17A) during L. pneumophila infection, and hematopoietic cell-derived IL-17A is known to be important for bacterial clearance. Thus, intratracheal administration of wild-type neutrophils or recombinant IL-17A restored bacterial clearance and neutrophil recruitment in Il17a(-/-) mice. Furthermore, neutrophil-depleted Rag2(-/-) and Rag2/Il-2rγ(-/-) mice exhibited increased bacterial burden, reduced neutrophil influx and IL-17A production in the lung. Recombinant IFN-γ administration in Il17a(-/-) mice augmented bacterial elimination, whereas IL-17A administration in Ifnγ(-/-) mice did not augment bacterial clearance. IFN-γ is produced by T cells, but not neutrophils or macrophages, suggesting that neutrophil-derived IL-17A induces IFN-γ in a paracrine fashion. Human pneumonic lungs and human neutrophils challenged with L. pneumophila exhibited increased numbers of IL-17A producing cells. These findings display a novel function of neutrophil-derived IL-17A in antibacterial defense via the induction of IFN-γ in a paracrine manner.
Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University (LSU), Baton Rouge, Louisiana, USA.
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Cai
Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University (LSU), Baton Rouge, Louisiana, USA.
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Batra
Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University (LSU), Baton Rouge, Louisiana, USA.
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Langohr
Center for Experimental Medicine and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, Japan.
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Iwakura
Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, School of Veterinary Medicine, Louisiana State University (LSU), Baton Rouge, Louisiana, USA.|Division of Pulmonary and Critical Care, Department of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
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Jeyaseelan
D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D058491:Bacterial Load; D002478:Cells, Cultured; D019281:Dimerization; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016952:Legionella pneumophila / Q000276:immunology*; D007877:Legionnaires' Disease / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D019899:Paracrine Communication
D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D007371:Interferon-gamma