RATIONALE: Acute respiratory distress syndrome (ARDS) is defined by the presence of systemic hypoxia and consequent upon disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.
OBJECTIVES: We aimed to test the hypothesis that during acute lung inflammation tissue production of pro-resolution type 2 cytokines (IL-4 and IL-13) dampen the pro-inflammatory effects of hypoxia through suppression of Hypoxia Inducible Factor (HIF-1)α-mediated neutrophil adaptation, resulting in resolution of the lung injury.
METHODS: Neutrophil activation of IL4Ra signaling pathways were explored ex vivo in human ARDS patient samples, in vitro following the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo, through the study of IL4Ra deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.
MEASUREMENTS AND MAIN RESULTS: IL-4 was elevated in human bronchoalveolar lavage from ARDS patients and its receptor was identified on inflamed lung neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α dependent hypoxic survival and limited pro-inflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent upon expression of the oxygen sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche, in contrast inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.
CONCLUSIONS: We describe an important interaction whereby IL4Rα-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil mediated acute lung injury. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/.
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Early online date||08 Mar 2019|
|Publication status||Early online date - 08 Mar 2019|