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Published on: May 21, 2018
Unveiling the Emerging Role of Extracellular Vesicle-Inflammasomes in Hyperoxia-Induced Neonatal Lung and Brain
Karen Young1, Merline Benny1, Augusto Schmidt1
1Division of Neonatology, Department of Pediatrics, Batchelor Children Research Institute, University of Miami School of Medicine, Miami, FL 33136, USA.
Insights
Extracellular vesicles (EVs) carrying inflammasomes mediate lung-to-brain communication, contributing to brain injury and neurodevelopmental impairment in premature infants with bronchopulmonary dysplasia. Targeting these EV-inflammasomes may offer new therapeutic strategies.
Area of Science:
- Neonatal physiology and pathology
- Immunology and molecular biology
- Neuroscience and developmental biology
Background:
- Extremely premature infants face high risks of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).
- The precise mechanisms linking BPD to brain injury and long-term NDI remain unclear.
- Extracellular vesicles (EVs) and inflammasomes are implicated in cellular communication and inflammatory responses.
Purpose of the Study:
- To review the role of EV-inflammasomes in mediating lung-to-brain crosstalk.
- To elucidate the contribution of EV-inflammasomes to BPD, neonatal brain injury, and NDI pathogenesis.
- To explore EV-inflammasomes as potential therapeutic targets.
Main Methods:
- Review of existing literature on EVs, inflammasomes, BPD, and neonatal brain injury.
- Analysis of studies investigating hyperoxia-induced lung and brain injury.
- Examination of research on EV cargo and their effects on neonatal brain.
Main Results:
- Hyperoxia stimulates the release of lung-derived EVs containing inflammasome components.
- Adoptive transfer of these EVs induces brain inflammatory injury in neonatal models.
- EV-inflammasomes mediate lung-to-brain crosstalk through EV-dependent and independent pathways.
Conclusions:
- EV-inflammasomes play a critical role in the pathogenesis of BPD-associated brain injury and NDI.
- Targeting EV-inflammasomes presents a promising therapeutic avenue for preventing or treating neonatal lung and brain injury.
Abstract:
Extremely premature infants are at significant risk for developing bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently unknown how BPD contributes to brain injury and long-term NDI in pre-term infants. Extracellular vesicles (EVs) are small, membrane-bound structures released from cells into the surrounding environment. EVs are involved in inter-organ communication in diverse pathological processes. Inflammasomes are large, multiprotein complexes that are part of the innate immune system and are responsible for triggering inflammatory responses and cell death. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activating inflammatory caspase-1. Activated caspase-1 cleaves gasdermin D (GSDMD) to release a 30 kD N-terminal domain that can form membrane pores, leading to lytic cell death, also known as pyroptosis. Activated caspase-1 can also cleave pro-IL-1β and pro-IL-18 to their active forms, which can be rapidly released through the GSDMD pores to induce inflammation. Recent evidence has emerged that activation of inflammasomes is associated with neonatal lung and brain injury, and inhibition of inflammasomes reduces hyperoxia-induced neonatal lung and brain injury. Additionally, multiple studies have demonstrated that hyperoxia stimulates the release of lung-derived EVs that contain inflammasome cargos. Adoptive transfer of these EVs into the circulation of normal neonatal mice and rats induces brain inflammatory injury. This review focuses on EV-inflammasomes' roles in mediating lung-to-brain crosstalk via EV-dependent and EV-independent mechanisms critical in BPD, brain injury, and NDI pathogenesis. EV-inflammasomes will be discussed as potential therapeutic targets for neonatal lung and brain injury.
