Abstract
Hypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1–5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immune-privileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage.
Highlights
Neonatal brain injury resulting from oxygen deprivation around the time of birth affects 1–3/1000 live term births in high-income countries with rates 5–10 times higher in low-resource setting
There is a considerable amount of information in respect to the role of the C system, but there is no direct evidence for the involvement of antimicrobial peptides (AMPs) in neonatal HI brain injury
Neonatal HI is associated with a robust inflammatory response, involving rapid change in neuronal gene expression associated with stimulation and aggregation of astrocytes and microglia for survival support [17]
Summary
Neonatal brain injury resulting from oxygen deprivation around the time of birth affects 1–3/1000 live term births in high-income countries with rates 5–10 times higher in low-resource setting. The early response IL-1, IL-6, and TNF-α cytokines are believed to be influential in the progression of injury in the immature brain via stimulation of synthesis of other cytokines and adhesion molecules, and prompting leukocyte infiltration, which in turn will lead to further recruitment of immune cells, as well as induction of neuronal injury mediators such as nitric oxide This continual and progressive stimulus has influencing modulatory effects on glial gene expression and activation. A neonatal mouse study of HI injury has demonstrated that mRNA expression of chemokines precedes infiltration of immune cells into the brain, proving its relevance in the inflammatory response following insult to the immature brain [31, 40]. HBD-4 was identified by genomics [66] and its expression has been assessed through detection of mRNA and considered to occur primarily in testis and
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