IL4Rα Signaling Abrogates Hypoxic Neutrophil Survival and Limits Acute Lung Injury Responses In Vivo.

Abstract

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood. Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1α (hypoxia-inducible factor-1α)-mediated neutrophil adaptation, resulting in resolution of lung injury. Methods: Neutrophil activation of IL4Ra (IL-4 receptor α) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after 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 BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1α-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on 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.

• Authors: Alison J Harris, Ananda S Mirchandani, Ruairi W Lynch, Fiona Murphy, Liam Delaney, Donna Small, Patricia Coelho, Emily R Watts, Pranvera Sadiku, David Griffith, Rebecca S Dickinson, Eilidh Clark, Joseph A Willson, Tyler Morrison, Massimilliano Mazzone, Peter Carmeliet, Bart Ghesquiere, Cecilia O'Kane, Danny McAuley, Steve J Jenkins, Moira K B Whyte, Sarah R Walmsley
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 200 Issue 2 Pg. 235-246 (07 15 2019) ISSN: 1535-4970 [Electronic] United States
• PMID: 30849228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• IL4R protein, human
• Il4ra protein, mouse
• Interleukin-4 Receptor alpha Subunit
• Receptors, Cell Surface
• STAT Transcription Factors
• Interleukin-4

Topics

• Acute Lung Injury (immunology, metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Hypoxia (immunology)
• Cell Survival (drug effects)
• Gene Expression Regulation
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Interleukin-4 (immunology, metabolism, pharmacology)
• Interleukin-4 Receptor alpha Subunit (genetics, immunology, metabolism)
• Mice
• Mice, Knockout
• Neutrophils (drug effects, immunology, metabolism)
• Receptors, Cell Surface (immunology, metabolism)
• Respiratory Distress Syndrome (immunology, metabolism)
• STAT Transcription Factors (metabolism)
• Signal Transduction