RT Journal Article
SR Electronic
T1 Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte–dendritic cell antigen presentation
JF Science Immunology
JO Sci. Immunol.
FD American Association for the Advancement of Science
SP eaax7006
DO 10.1126/sciimmunol.aax7006
VO 4
IS 41
A1 Patel, Dhiren F.
A1 Peiró, Teresa
A1 Bruno, Nicoletta
A1 Vuononvirta, Juho
A1 Akthar, Samia
A1 Puttur, Franz
A1 Pyle, Chloe J.
A1 Suveizdytė, Kornelija
A1 Walker, Simone A.
A1 Singanayagam, Aran
A1 Carlin, Leo M.
A1 Gregory, Lisa G.
A1 Lloyd, Clare M.
A1 Snelgrove, Robert J.
YR 2019
UL http://immunology.sciencemag.org/content/4/41/eaax7006.abstract
AB Allergic airway inflammation is a complex disease, and multiple immune and nonimmune contribute to development and progression. Here, using a house dust mite–induced mouse model of allergic inflammation, Patel et al. report that depletion of neutrophils worsens airway inflammation. Neutrophil depletion, as expected, led to enhanced myelopoiesis that was driven by granulocyte colony-stimulating factor (G-CSF). By carrying out experiments to understand how neutrophil depletion and systemic increase in G-CSF levels drive airway inflammation, the authors have uncovered a previously unsuspected link between G-CSF and type 2 innate lymphoid cells (ILC2s). They report that G-CSF acts directly on both human and mouse ILC2s to promote production of TH2 cytokines interleukin-5 (IL-5) and IL-13.Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.