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. [Display omitted] •A maternal high-fat diet promotes low-grade systemic inflammation (LGSI) in the offspring•Increased hepatic neutropoiesis underpins the elevated sIL-6R, IL-6, and IL-17A production•Blockade of IL-6 trans-signaling protects against severe respiratory infection and asthma Curren and Ahmed et al. demonstrate that a maternal high-fat diet predisposes the offspring to low-grade systemic inflammation (LGSI), severe lower respiratory tract infections, and later asthma. Blockade of IL-6 trans-signaling, increased by elevated and persistent hepatic neutropoiesis in early life, confers protection against severe lower respiratory tract infections and subsequent asthma.