A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling
Bodie Curren,
Tufael Ahmed,
Ridwan B. Rashid,
Ismail Sebina,
Md. Al Amin Sikder,
Daniel R. Howard,
Mariah Alorro,
Md. Ashik Ullah,
Alec Bissell,
Muhammed Mahfuzur Rahman,
Michael A. Pearen,
Grant A. Ramm,
Antiopi Varelias,
Stefan Rose-John,
Kelli P.A. MacDonald,
Robert Hoelzle,
Páraic Ó Cuív,
Kirsten M. Spann,
Paul G. Dennis,
Simon Phipps
Affiliations
Bodie Curren
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Tufael Ahmed
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia
Ridwan B. Rashid
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Ismail Sebina
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Md. Al Amin Sikder
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Daniel R. Howard
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Mariah Alorro
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Md. Ashik Ullah
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Alec Bissell
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Muhammed Mahfuzur Rahman
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Michael A. Pearen
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
Grant A. Ramm
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Antiopi Varelias
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, QLD 4072, Australia
Stefan Rose-John
Christian-Albrechts-Universität zu Kiel, Medical Faculty, Olshausenstraße 40, 24098 Kiel, Germany
Kelli P.A. MacDonald
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia
Robert Hoelzle
School of Environment, The University of Queensland, QLD 4072, Australia
Páraic Ó Cuív
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia
Kirsten M. Spann
Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia
Paul G. Dennis
Australian Infectious Diseases Research Centre, The University of Queensland, QLD 4072, Australia; School of Environment, The University of Queensland, QLD 4072, Australia
Simon Phipps
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, QLD 4072, Australia; Corresponding author
Summary: A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver. Inhibition of IL-6 trans-signaling using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.
