Lactylation may be a Novel Posttranslational Modification in Inflammation in Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

Perinatal hypoxia-ischemia remains the most common cause of acute neonatal brain injury and is associated with a high death rate and long-term neurological abnormalities such as memory and cognitive deficits and dyskinesia. Hypoxia-ischemia triggers an inflammatory cascade in the brain that is amplified by the activation of immune cells and the influx of peripheral immune cells into the brain parenchyma in response to cellular injury. Thus, acute cerebral hypoxic-ischemic inflammation is a major contributor to the pathogenesis of newborn hypoxic-ischemic brain injury. Lactate is a glycolysis end product that can regulate inflammation through histone lactylation, a unique posttranslational modification that was identified in recent studies. The purpose of this review is to outline the recent improvements in our understanding of microglia-mediated hypoxic-ischemic inflammation and to further discuss how histone lactylation regulates inflammation by affecting macrophage activation. These findings may suggest that epigenetic reprogramming-associated lactate input is linked to disease outcomes such as acute neonatal brain injury pathogenesis and the therapeutic effects of drugs and other strategies in relieving neonatal hypoxic-ischemic brain injury. Therefore, improving our knowledge of the reciprocal relationships between histone lactylation and inflammation could lead to the development of new immunomodulatory therapies for brain damage in newborns.

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes

“…High levels of lactate and pyruvate can increase the production of reactive oxygen species (ROS) and inflammatory mediators, damage the blood–brain barrier (BBB), and lead to edema. These changes eventually result in sustained neuronal damage within 6–48 h post-injury [ 13 , 21 , 50 , 51 ]. Consistent with this, we also observed elevated levels of pyruvate and lactate in the hippocampal tissue of acute HI mice, indicating a greater reliance on glycolysis by the cells.…”

A new strategy for osteoarthritis therapy: Inhibition of glycolysis

“…It has been found that lactate reduces M1 macrophage activation and promotes M2 macrophage polarization by modifying histones in the inflammatory response ( Zhang et al, 2019 ; Ivashkiv, 2020 ). Further studies on histone lactation may lead to new therapeutic targets for OA treatment and strategies for resolving inflammation ( Zhou et al, 2022 ). The activity and expression of LDH are significantly increased in primary chondrocytes treated with IL-1β.…”

Ketogenic Diet for Neonatal Hypoxic–Ischemic Encephalopathy

“…The pathophysiology of HIE is complex and remains poorly understood. However, dysfunction of mitochondrial and cerebral glucose metabolism has been identified as a key factor . In mitochondria, KBs can act as alternative substrates for ATP production .…”

“…However, dysfunction of mitochondrial and cerebral glucose metabolism has been identified as a key factor. 27 In mitochondria, KBs can act as alternative substrates for ATP production. 28 In addition, free fatty acids are converted to KBs, which are then converted to acetyl-CoA and enter the Krebs cycle.…”