Microglia plasticity in a mouse model of Fabry disease
Basic Science: Pain Models
Jeiny Luna-Choconta Medizinische Universität Innsbruck, Austria
Jeiny Luna-Choconta, Medizinische Universität Innsbruck, Austria
Michaela Kress, Medizinische Universität Innsbruck, Austria
Michiel Langeslag, Medical University of Innsbruck, Austria
Background and Aims:
Lysosomal storage disorders (LSD) activate immune responses and an early life neuropathic pain phenotype is developed. Fabry disease (FD) is a LSD caused by deficiency in the x-chromosomal ?-galactosidase A (?Gal) gene, leading to the accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb3). Recent evidence suggests that neuropathic pain is associated with alterations and dysfunction of neurons and non-neuronal cells in the pain pathway. The importance of neuroimmune interactions in FD neuropathic pain is incompletely understood. Therefore, we aimed to explore the role of macrophages and microglial cells during the progression of FD in the dorsal root ganglion, the spinal cord and brain in a murine transgenic ?-Gal A-/0 (GLAko) model of FD.
We characterized the morphology of microglial cells in young, adult and old male mice. Vibratome sections were incubated with rabbit anti-Tmem119 antibody. Multiphoton microscopy was used and z-stack images acquired from different anatomical regions (hippocampus CA1, dentate gyrus and spinal cord). Images were analyzed by Imaris 9.3 software (Bitplane) using filament tracers and surface modules to generate the reconstruction images followed by Sholl analysis. Statistics test were one-way ANOVA by pairwise comparison (P < 0.05) with post-hoc Bonferroni correction and linear mixed models.
The morphology of the microglia has been key in analyzing its dynamics in an inflammatory response to different stimuli. The overall density of microglia in different brain regions was similar in wt and GLAko mice. However, we observed that the number of intersections of microglial processes was altered in advanced stages of FD (52 weeks, male mice). Being a progressive disease, it is possible that the morphological changes are highly plastic at each stage of FD. Nevertheless, we consider early and late stages as the most critical points of the disease, when accumulating glycosphingolipids strongly affect both the peripheral and central nervous system and cause hyper- and hyposensitivity, respectively.
Neuroimmune interactions play an important role in the development of neuropathic pain in several disorders, and resident brain macrophages and microglia are essential cell populations contributing to the disease pathogenesis. Microglia and macrophages are suggested to be relevant components also for neurological deficits developing during FD progression.
Conflicts of Interest:
Source of Financial Support for the Project:
TOBeATPAIN project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie Grant Agreement No 764860.