Innate Lymphoid Cells Are the Predominant Source of IL-17A during the Early Pathogenesis of Acute Respiratory Distress Syndrome.
BACKGROUND
IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Although IL-17A is the archetypal cytokine of T-helper 17 cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.


OBJECTIVE
To identify the cellular source and the role of IL-17A in the early phase of lung injury.


METHODS
Lung injury was induced in wild-type (C57BL/6) and IL-17 knockout (KO) mice with aerosolized 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 performed by flow cytometry.


RESULTS
A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared with wild-type mice. The majority of RORγt(+) cells in the mouse lung were the recently identified group 3 innate lymphoid cells (ILC3s). Detailed characterization 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 recombinase-activating gene 2 KO mice, which lack T cells but retain innate lymphoid cells. No amelioration of pathology was observed in the recombinase-activating gene 2 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 pILC3s. Modulation of the activity of pILC3s may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Roshell
R
Muir
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Megan
M
Osbourn
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Alice V
AV
Dubois
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Emma
E
Doran
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Donna M
DM
Small
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Avril
A
Monahan
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Cecilia M
CM
O'Kane
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Katherine
K
McAllister
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Denise C
DC
Fitzgerald
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Adrien
A
Kissenpfennig
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.|2 Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, United Kingdom.
Daniel F
DF
McAuley
1 Centre for Infection and Immunity, Queen's University Belfast, Belfast, United Kingdom; and.
Rebecca J
RJ
Ingram
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000096:biosynthesis*; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000473:pathology*
D020381:Interleukin-17
IL-17; acute lung injury; acute respiratory distress syndrome; group 3 innate lymphoid cell; lymphocyte