Innate Lymphoid Cells are the Predominant Source of Interleukin-17A During the Early Pathogenesis of Acute Respiratory Distress Syndrome

Roshell Muir, Megan Osbourn, Alice V. Dubois, Emma Doran, Donna M. Small, Avril Monahan, Cecilia M. O'Kane, Katherine McAllister, Denise C. Fitzgerald, Adrien Kissenpfennig, Daniel F. McAuley, Rebecca J. Ingram

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)
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Abstract

Rationale: IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Whilst IL-17A is the archetypal cytokine of T helper (Th)17 cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.

Objectives: To identify the cellular source and the role of IL17A in the early phase of lung injury

Methods: Lung injury was induced in WT (C57BL/6) and IL-17 KO mice with aerosolised LPS (100 µg) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing RORγt, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was carried out by flow cytometry.

Measurement and Main Results: A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared to wild type (WT) mice. The majority of RORγt+ cells in the mouse lung were the recently identified type 3 innate lymphoid cells (ILC3). Detailed characterisation revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in Rag2 KO mice which lack T cells but retain ILCs. No amelioration of pathology was observed in the Rag2 KO mice.

Conclusions: IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3 cells. Modulation of pILC3s’ activity may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.
Original languageEnglish
Pages (from-to)407-416
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume193
Issue number4
Early online date21 Dec 2015
DOIs
Publication statusPublished - 15 Feb 2016

Keywords

  • ARDS, acute lung injury, IL-17, lymphocyte, ILC3, pILC

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