Effects of neuroinflammation on microglial nuclear morphology and nuclear lamina composition

Abstract

Microglia are resident macrophages of the central nervous system playing a vital role in brain development, homeostasis, tissue repair and disease response, making their study essential for understanding neurological disorders. Microglial cells exist in a resting state and maintain homeostasis until they are activated by factors derived from nervous system damage following infection, traumatic brain injury, stroke, or disease. Microglial activation results in changes in their migration, metabolism, and morphology. This induces the secretion of pro-inflammatory mediators often detrimental to the surrounding tissue, contributing to neurodegeneration. However, the effects of activation on microglial nuclei have remained understudied. It is important to understand what kinds of changes occur in the nucleus when homeostasis is disturbed, as nuclear changes can influence gene expression, cellular function, and the overall inflammatory response, shedding light on microglial mechanisms in disease progression.

The aim of this thesis was to study the changes in the nuclear morphology and nuclear lamina composition in human induced multipotent stem cell-derived microglial cells as a result of inflammatory activation. Inflammatory activation was induced with lipopolysaccharide. Microglial cells were immunostained for chromatin and nuclear A and B-type lamins, followed by quantitative analysis of their respective intensities and nuclear shape parameters. The analyses indicated that the lipopolysaccharide treatment induced smaller nuclei with increased membrane ruffling and increased intensity of chromatin and A- and B-type lamins but preserved the lamin A/C-to-lamin B intensity ratio. These suggest that eliciting a systemic inflammatory response shrinks the nuclei and influences chromatin organisation. Additionally, the increased lamin intensities might indicate changes in lamin-mediated interactions in the deformed nuclei.

This study shows that the lipopolysaccharide-induced inflammatory response has a significant impact on the nucleus and chromatin of microglia. The detected changes in the microglial nuclear morphology could play a role in the mechanisms of neurodegenerative response to damage or infection in the brain. This study therefore paves the way for future studies to better understand the role of nuclear dynamics in neurodegenerative disorders.