IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development

Abstract

Inflammation in the developing preterm lung leads to disrupted airway morphogenesis and chronic lung disease in human neonates. However the molecular mechanisms linking inflammation and the pathways controlling airway morphogenesis remain unclear. Here we show that IL-1β released by activated fetal lung macrophages is the key inflammatory mediator that disrupts airway morphogenesis. In mouse lung explants, blocking IL-1β expression, post-translational processing, and signaling each protected the formation of new airways from the inhibitory effects of E. coli LPS. Consistent with a critical role of IL-1β, mice expressing a gain of function Nlrp3 allele and subsequent overactive inflammasome activity displayed abnormal saccular stage lung morphogenesis and died soon after birth. While the early stage fetal lung appeared capable of mounting an NF-κB mediated immune response, airway formation became more sensitive to inflammation later in development. This period of susceptibility coincided with higher expression of multiple inflammasome components, which could therefore increase the capability to release bioactive IL-1β. Macrophages from Nlrp3 gain of function mice also expressed higher levels of more mature cell surface markers, additionally linking inflammasome activation with macrophage maturation. These data identify developmental expression of the inflammasome and IL-1β release by fetal lung macrophages as key mechanisms and potential therapeutic targets for neonatal lung disease.

Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

“…Importantly, multiple clinical studies have associated elevated IL1β with an increased risk of developing BPD ( 2 , 3 ). While pre-clinical studies suggest that IL1β contributes to abnormal lung development after inflammatory insult, including hyperoxia, endotoxemia and the combination of hyperoxia and endotoxemia ( 8 – 12 , 14 – 16 ). Furthermore, blocking IL1β activity with IL1 receptor antagonists prevents lung injury and preserves lung development after inflammatory insult ( 14 – 16 ).…”

“…Understanding the mechanisms that link the innate immune response to neonatal lung injury is key to developing targeted anti-inflammatory therapies that minimize detrimental off-target effects. Multiple clinical and pre-clinical studies implicate the pro-inflammatory cytokine IL1β in the pathogenesis of BPD ( 2 , 3 , 8 – 12 ). To date, interventions to attenuate the pro-inflammatory effects of IL1β have targeted events downstream of increased gene expression.…”

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

“…We showed that in homeostasis, lymphoid cells expand during late lung development, becoming the prevalent immune cell type of the lung, whereas under hyperoxic conditions, myeloid cells remained the major immune cell type. The role of immune cell signaling, such as IL-1b 62 , IFNγ 63 and TGFβ 64 , as well as the NRLP3 inflammasome 65 , has been investigated in impaired lung development by several studies.…”

Loss of TAB3 expression by shRNA exhibits suppressive bioactivity and increased chemical sensitivity of ovarian cancer cell lines via the NF‐κB pathway

“…It has been well demonstrated that the transcription factor NF‐κB plays a pivotal role in the regulation of diverse physiological and pathological processes, including immune response, inflammation and cancer development . In order to keep homeostasis, NF‐κB activation process must be tightly controlled.…”