Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain

Abstract

BackgroundIntrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy.MethodsTo create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1–5 and myelination was assessed.ResultsHere, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation.ConclusionsIn this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.

Mechanism of Intestinal Flora and Proteomics on Regulating Immune Function of Durio zibethinus Rind Polysaccharide

“…The Th1 and Th2 subgroups of mice can secrete IL-2 and IL-4, respectively, and both IL-2 and IL-4 can promote the proliferation of T cells [43,44]. In addition, IL-4 can also promote the expression of B cells, enhance the antigen presentation ability of B cells, increase IgG1 and IgE levels, and make the responses of immune system to antigen stimulation [45,46]. Gong et al found that Bletilla baicalensis polysaccharides could significantly enhance the levels of IL-2 and IL-4 in immunosuppressed mice [47] which is similar with the effect of DZMP in this paper.…”

The impact of trophic and immunomodulatory factors on oligodendrocyte maturation: Potential treatments for encephalopathy of prematurity

“…All in all these anti‐inflammatory cytokines contribute to a more favorable environment for neuronal and oligodendrocyte survival (Yang et al, 2009). Although protection by IL‐4 and IL‐10 is believed to be largely mediated through their role in dampening adverse inflammatory events, IL‐4 and IL‐10 can also directly target their respective receptors present on cells of the oligodendrocyte‐lineage (Molina‐Holgado, Vela, Arevalo‐Martin, & Guaza, 2001; Zanno et al, 2019). Intracellularly, IL‐10 activates the JAK/STAT and PI3k/Akt pathways (see Box 2; Zhou, Peng, Insolera, Fink, & Mata, 2009) while it is known IL‐4 targets PPARγ in OPCs, potentially through STAT6 (Zanno et al, 2019; Zhang et al, 2019).…”

“…Specifically, oligodendrogenesis is instigated via IGF‐1 production by IL‐4‐conditioned microglia (Butovsky et al, 2006). The studies on direct effects of IL‐4 on OLs are conflicting as some studies find no direct effects of IL‐4 on cells of the oligodendrocyte‐lineage in vitro (Butovsky et al, 2006; Psachoulia et al, 2016), others report inhibition of differentiation of these cells (Zanno et al, 2019) or stimulation of OPC differentiation through transcription factor PPARγ (Zhang et al, 2019).…”

“…It has been shown that IL‐4 may elicit a different response in neonates versus adults in in vivo experimental models. In a rat model of intrauterine growth restriction, IL‐4 was significantly increased in the brain of growth‐restricted pups, and treatment with a neutralizing IL‐4 antibody directly after birth improved oligodendrocyte maturation and white matter development, by decreasing the Th2 neuroinflammatory response (Zanno et al, 2019). In contrast, IL‐4‐based therapies show great promise in regenerating white matter in models of adult inflammatory brain injury (Zhang et al, 2019).…”

White matter and neurodevelopmental disorders: honoring Jean De Vellis through the work of the NICHD-funded intellectual and developmental disabilities research centers

“…In addition to investigations of white matter morphology, a key aspect of thinking about novel treatments has come from thinking about inflammation and the negative impact this may have on neurodevelopment. Investigators at the Children's Hospital of Philadelphia IDDRC present exciting work demonstrating that inflammation caused by Th2 cytokines during early brain development can be rescued with the application of IL-4 antibody treatment in the newborn rat [5]. This work highlights the importance of the immune system and impact on white matter development.…”