Search

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., Competing Interests: Declaration of interests S.R.-J. has acted as a consultant for AbbVie, Chugai, Roche, Regeneron, Genentech Roche, Pfizer, Sanofi, and I-Mab Biopharma regarding the use of interleukin-6 blockade with other agents. He is a member of the supervisory board of the CONARIS Research Institute. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein olamkicept together with Ferring Pharmaceuticals and I-Mab Biopharma. S.R.-J. has stock ownership in CONARIS. G.A.R. is a member of the board of genomiQa., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)