Modulatory effect of IL‐1 inhibition following lipopolysaccharide‐induced neuroinflammation in neonatal microglia and astrocytes

Abstract

Introduction: Inflammation-induced white matter injury (WMI) in preterm infants is characterized by microglia activation, astrogliosis, oxidative stress and neurodevelopmental impairments. Microglia and astrocytes activation can be described under a broad spectrum of activation profile with extremes described as pro-inflammatory/neurotoxic (M1 microglia or A1 astrocyte) or anti-inflammatory/neuroprotective (M2 microglia or A2 astrocyte) in response to stimuli including lipopolysaccharide (LPS) and interleukin 1 (IL-1). As IL-1 signalling pathway has been posited as a major driver of inflammationinduced perinatal WMI, our aim was to evaluate the contribution of IL-1 modulation in LPS-induced microglia and astrocyte activation. Methods: Primary neonatal cell co-cultures of astrocytes and microglia were treated with LPS (100 ng/ml) for 8 h or 24 h. Two distinct IL-1 receptor antagonists, Rytvela or Kineret (1 μg/ml), were added simultaneously with LPS to respectively modulate or block IL-1 receptor. Medium was collected to measure levels of IL-1β. Expression of markers related to pro-and antiinflammatory microglia and astrocyte activation profiles and antioxidant genes were assessed. Results: At 8 h, LPS exposure induced pro-(M1/A1) and anti-inflammatory (M2/A2) marker expression and inhibited antioxidant gene expression in microglia and astrocytes. By 24 h, continuous LPS exposure increased proinflammatory and neurotoxic microglial and astrocytic markers (M1/A1), as well as antioxidant genes.

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

“…Therefore, the neurotoxic A1 astrocytes shown here could be induced by the activated microglia [5]. In agreement with previous reports [5,39], we also confirmed that LPS induced neurotrophic A2 astrocytes because they were double-positive to S100A10 and GFAP, suggesting the activation of anti-inflammatory mechanisms. Accordingly, after LPS stimulation, S100A10 protein in complex with the Ca 2+ /lipid-binding protein annexin A2 (annexin A2-S100A10 complex) [40] inhibits astrocytic proliferation and modulates inflammasome activation as well as cytokines released in the CNS [41].…”

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

“…For example, Homer1, a scaffolding protein of PSD, has been observed to be downregulated during oxidative stress and neuroinflammation [ 222 ]. Homer1 suppresses the A1 deleterious astrocytic phenotype and promotes the conversion to A2 astrocytes, which are neuroprotective by producing anti-inflammatory cytokines and neurotrophic factors [ 217 ]. Therefore, the abnormalities in PSD induced by inflammatory conditions may alter the phenotypic polarization of neighboring astrocytes, which in turn, not providing support to neuron clusters, leads to a feedback loop that reverberates on the synapse.…”