A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling
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.
Authors
- Md Ashik Ullah (ORCID: https://orcid.org/0000-0002-0025-1796)
- Grant A. Ramm (ORCID: https://orcid.org/0000-0001-7058-6201)
- Alec Bissell (ORCID: https://orcid.org/0000-0001-8388-7118)
- Páraic Ó Cuív (ORCID: https://orcid.org/0000-0002-1625-633X)
- Md Al Amin Sikder (ORCID: https://orcid.org/0000-0003-0663-2415)
- Daniel R. Howard (ORCID: https://orcid.org/0000-0002-2121-8362)
- Paul G. Dennis (ORCID: https://orcid.org/0000-0002-4895-3105)
- Ismail Sebina (ORCID: https://orcid.org/0000-0003-3232-3472)
- Muhammed Mahfuzur Rahman (ORCID: https://orcid.org/0000-0002-2077-7189)
- Michael A. Pearen (ORCID: https://orcid.org/0000-0002-9401-191X)
- Bodie F. Curren (ORCID: https://orcid.org/0000-0002-1165-6406)
- Kirsten Spann (ORCID: https://orcid.org/0000-0003-0567-8382)
- Robert D. Hoelzle (ORCID: https://orcid.org/0000-0001-5131-8041)
- Simon Phipps (ORCID: https://orcid.org/0000-0002-7388-3612)
- Mariah Alorro (ORCID: https://orcid.org/0000-0002-2098-2801)
- Kelli P. A. MacDonald (ORCID: https://orcid.org/0000-0003-3451-4221)
- Tufael Ahmed (ORCID: https://orcid.org/0000-0002-0378-6542)
- Antiopi Varelias (ORCID: https://orcid.org/0000-0002-3437-9659)
- Stefan Rose‐John (ORCID: https://orcid.org/0000-0002-7519-3279)
- Ridwan Bin Rashid (ORCID: https://orcid.org/0000-0001-5095-8848)
Institutions
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Christian-Albrechts-Universität zu Kiel (DE)
- Queensland Department of Environment and Science (AU)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114974
- Citations
- 2
- Primary Topic
- Neonatal Respiratory Health Research
- Type
- article
- Field-Weighted Citation Impact
- 0.84
Funders
- National Health and Medical Research Council