The human microglia responsome: a resource to better understand microglia states in health and disease

Abstract

Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are as yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human microglial cells from 67 different donors (N = 398 samples) at the gene and transcript level. We show that microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We observed a greater overlap between human stimulated microglia and human monocytes than with mouse microglia. We define specific microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer's disease (AD) genetic studies and microglia by integrating our inflammatory gene expression profiles with common genetic variants to map cis-expression QTLs (eQTLs). Together, we provide the most comprehensive transcriptomic database of the human microglia responsome.

Regional Microglial Response in Enthorino-hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

“…The phenotyping of astrocytes and microglia in CNS disease reveals distinct patterns based on their anatomical locations, as demonstrated through transcriptional, genetic, morphological, and metabolic activities [2] [3] [4]. Furthermore, the sensome of human microglia from various brain regions exhibits unique reactions to inflammatory stimuli, which change rapidly [5]. This introduces time as a critical variable in such studies, underscoring the dynamic nature of glial responses in the context of CNS disorders.…”

ER and SOCE Ca2+signals are not required for directed cell migration in human microglia

“…Primary cell cultures derived from rodent models have been the tools of choice for investigating the pathophysiological features of the cells of the CNS. However, growing transcriptomic and functional evidence indicates that critical species-specific differences exist among the different cell types of the CNS, with variations being prominent in non-neuronal cells like microglia [22,23]. Of note, microglia species-related differences appear to be further exacerbated in pathological settings, likely when the cells are engaged to counteract disease-associated challenges [24,25], thereby limiting the translation of current findings to human-related settings.…”

Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

“…The phenotyping of astrocytes and microglia in CNS disease reveals distinct patterns based on their anatomical locations, as demonstrated through transcriptional, genetic, 2 of 13 morphological, and metabolic activities [6,7]. Furthermore, the sensome of human microglia from various brain regions exhibits unique reactions to inflammatory stimuli, which change rapidly [8,9]. This introduces time as a critical variable in such studies, underscoring the dynamic nature of glial responses in the context of CNS disorders.…”