Interleukin-1: an important target for perinatal neuroprotection?

Abstract

Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy. Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth. Multiple pathways are involved in the pathogenesis of perinatal inflammation. However, studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1. In this review, we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury. We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage, and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist, anakinra, as a safe and effective therapeutic intervention. We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment, and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.

Keywords: brain; inflammation; interleukin-1; interleukin-1 receptor antagonist; interleukin-1β; neonatal encephalopathy; neuroprotection; preterm brain injury.

Figure 1

Innate immune stimulant-induced activation and signaling of IL-1β in brain (top) and circulation (bottom), and effects of endogenous and exogenous IL-1Ra. Cerebral recognition of pathogen-associated molecular patterns (PAMPS) such as LPS by innate immune receptors, such as toll-like receptor 4 (TLR4) on microglia (purple), astrocytes (green), and other immune cells, leads to nuclear factor kappa B transcription of IL-1β. Consequently, the Pro-IL-1β protein is expressed intracellularly. The NOD-LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasome complex cleaves pro-caspase 1 into caspase 1 which in turn cleaves pro-IL-1β into bioactive IL-1β, which is then secreted by the cell. Bioactive IL-1β reacts with the IL-1 heterodimeric receptor (IL-1R1:IL-1R3) on the surface of most cell types including other microglia, astrocytes, oligodendrocytes (orange), and neurons (pink), and leads to further nuclear factor kappa B regulated transcription of IL-1β and the subsequent release of bioactive IL-1β. Increased protein expression levels of IL-1β cause activation of astrocytes, as well as cell damage and apoptosis of oligodendrocytes and neurons. By contrast, the endogenous IL-1 receptor antagonist (IL-Ra) secreted by microglia, and administration of recombinant exogenous IL-1Ra, bind to the IL-1R1: IL-1R3 receptor complex and thereby block activation of transcription factors. In the circulation, LPS is detected by TLR4 on macrophages (purple), and the same IL-1β signaling cascade releases IL-1β into the circulation which recruits additional immune cells and can further damage the endothelium. The endogenous IL-1 receptor antagonist IL-1Ra released by macrophages and other immune cells, and recombinant exogenous IL-1Ra blocks IL-1 signaling. Created with BioRender.com.