Intranasal IL-4 Administration Alleviates Functional Deficits of Periventricular Leukomalacia in Neonatal Mice.

Lin-Chao Yu,Qi-Xiong Chen,Wei-Bin Li,Jing-Kun Miao,Na Chen

doi:10.3389/fneur.2020.00930

Abstract

Background: Periventricular leukomalacia (PVL) is the major form of brain injury in premature infants. Currently, there are no therapies to treat PVL. Several studies suggested that polarization of microglia, a resident macrophage-like immune cell in the central nervous system, plays a vital role in brain injury and recovery. As an important mediator of immunity, interleukin-4 (IL-4) has critical effects on many immune cells, such as astrocytes and microglia. Increasing evidence shows that IL-4 plays a well-established role in attenuating inflammation in neurological disorders. Additionally, as a noninvasive and highly effective method, intranasal drug administration is gaining increasing attention. Therefore, in our study, we hypothesized that intranasal IL-4 administration is a promising strategy for PVL treatment.Methods: The therapeutic effects of IL-4 on neuroprotection were evaluated using a Control group, Hypoxia group, and Hypoxia + IL-4 treatment group. The PVL mouse model was established by a severe acute hypoxia (SAH) protocol. Exogenous IL-4 was intranasally administered to investigate its neuroprotective effects. A functional study was used to investigate neurological deficits, immunohistochemical technology and Western blotting were used to detect protein levels, and electron microscopy was used to evaluate myelination.Results: The results suggested that hypoxia stimulated Iba1+ microglial activation, downregulated myelin-related gene (NG2, MAG, and MBP) expression, reduced MBP protein levels, and caused neurological deficits. However, the intranasal administration of exogenous IL-4 partially inhibited Iba1+ microglial activation, improved myelination, and alleviated neurological deficits. The mechanistic study showed that IL-4 improved myelination possibly through the IL-4Ra-mediated polarization of microglia from the M1 phenotype to the M2 phenotype.Conclusion: In summary, our findings demonstrated that the intranasal administration of exogenous IL-4 improves myelination and attenuates functional deficits in a hypoxia-induced PVL model. Intranasal IL-4 administration may be a promising strategy for PVL treatment, for which further mechanistic studies are urgent.

Highlights

According to the WHO’s estimates, births of very preterm infants account for more than 2% of all live births, and the survival rates of these infants are more than 85% [1, 2], which is owing to advancements in obstetric and neonatal care [3]
We established the preterm periventricular leukomalacia (PVL) model by placing mice in severe acute hypoxia or room air conditions, according to the methods described by Clayton et al with brief modification [33]
hypoxia-induced saline-treated group (Hypoxia) dramatically decreased the expression of myelin basic protein (MBP) in the white matter area of P4 mice compared to that in the white matter area of Control mice as determined by Western blotting (Figure 1B) and immunohistochemistry (Figures 1C,E,F)

Summary

Introduction

According to the WHO’s estimates, births of very preterm infants (before 32 weeks of gestation) account for more than 2% of all live births, and the survival rates of these infants are more than 85% [1, 2], which is owing to advancements in obstetric and neonatal care [3]. Diffuse white matter injury is the most common form of injury in preterm birth infants, especially in infants with very low birth weights, and it is a condition that leads to periventricular leukomalacia (PVL) [8, 9]. Some studies have found that activated microglia, at least in the initial phase after injury, are involved in injury to immature white matter. After acute injury, some microglia, such as those with M2 phenotypes (M2a and M2c), might promote injury repair by being involved in late anti-inflammatory responses [21, 22]. Several studies suggested that polarization of microglia, a resident macrophage-like immune cell in the central nervous system, plays a vital role in brain injury and recovery. In our study, we hypothesized that intranasal IL-4 administration is a promising strategy for PVL treatment

Methods

Results

Discussion

Conclusion