IFN-γ induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense

Abstract

The role of 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 (i.t) administration of WT 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.

Role of Dectin‐1 receptor on cytokine production by human monocytes challenged with Paracoccidioides brasiliensis

“…We also observed that monocytes were able to produce IL‐17A after the challenge with fungus, and this production was related to Dectin‐1, once the receptor blockage reduced the IL‐17A levels. GM‐CSF activation also led to an increase in IL‐17 production, in agreement with some studies showing the participation of phagocytic cells on IL‐17 production . Recently, it was demonstrated that the most severe form of PCM presents a response characterised by Th2/Th9 cells, whereas the milder and chronic inflammatory response presents a predominance of Th17 cells, with an important participation of Th1 cells .…”

The many faces of interleukin-17 in inflammatory skin diseases

“…The prototype is fungi, although IL‐17 contributes also to the host defence against both Gram‐negative and Gram‐positive bacteria . Neutrophils produce IL‐17A as an early host defence mechanism, which further triggers interferon (IFN)‐γ production providing bacterial clearance . IL‐17A has a strong inflammatory capacity and induces subsequent cytokine and chemokine release.…”

“…In contrast, IL‐17E, also termed IL‐25, influences type 2 immunity and inhibits Th17‐mediated inflammation. The functions of IL‐17B, IL‐17C and IL‐17D remain currently under investigation …”

Microbiota-specific Th17 Cells

“…73, 74 IL-17 has been demonstrated to induce production of β-defensin 2 (hBD-2), hBD-3, S100A7, S100A8, and S100A9. IL-17F, on the other hand, potently promote the transcription of hBD-2, S100A8 and S100A9.…”