Microglial Morphology Across Distantly Related Species: Phylogenetic, Environmental and Age Influences on Microglia Reactivity and Surveillance States

Abstract

Microglial immunosurveillance of the brain parenchyma to detect local perturbations in homeostasis, in all species, results in the adoption of a spectrum of morphological changes that reflect functional adaptations. Here, we review the contribution of these changes in microglia morphology in distantly related species, in homeostatic and non-homeostatic conditions, with three principal goals (1): to review the phylogenetic influences on the morphological diversity of microglia during homeostasis (2); to explore the impact of homeostatic perturbations (Dengue virus challenge) in distantly related species (Mus musculus and Callithrix penicillata) as a proxy for the differential immune response in small and large brains; and (3) to examine the influences of environmental enrichment and aging on the plasticity of the microglial morphological response following an immunological challenge (neurotropic arbovirus infection). Our findings reveal that the differences in microglia morphology across distantly related species under homeostatic condition cannot be attributed to the phylogenetic origin of the species. However, large and small brains, under similar non-homeostatic conditions, display differential microglial morphological responses, and we argue that age and environment interact to affect the microglia morphology after an immunological challenge; in particular, mice living in an enriched environment exhibit a more efficient immune response to the virus resulting in earlier removal of the virus and earlier return to the homeostatic morphological phenotype of microglia than it is observed in sedentary mice.

Microglial morphology in the somatosensory cortex across lifespan. A quantitative study

“…[1][2][3] They will display changes starting from polarized morphologies via rounded cell bodies all the way to amoeboid shape upon detecting tissue damage. 15,41,42 Also, in the presence of amyloid beta in the parenchyma microglia can display less branching and a reduced arborized area 7 and will cluster around blood vessels in case of a blood barrier disruption. 43 As such, determining the exact microglia morphology at a certain age can provide insights into the overall homeostasis of the CNS, as any change in the microenvironment of the cells will be detected and a morphological remodeling will occur.…”

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

“…Microglia, the immune cells of the CNS, are first responders following injury. Under homeostatic conditions microglia have a ramified morphology and sample the microenvironment for any perturbations in the spinal cord [ 139 , 140 , 141 ]. Following SCI, microglia and infiltrating macrophages, hereafter referred to as “microglia”, retract their processes and adopt an ameboid morphology in response to cytokines released from damaged cells in the parenchyma, such as interleukin 1ß (IL-1ß), tumor necrosis factor α (TNFα, interferon-γ (IFN-γ), adenosine triphosphate (ATP), and nitric oxide (NO) [ 140 ].…”

“…Activated microglia are proliferative cells that themselves release pro-inflammatory cytokines such as IL-1ß, IL-12, TNFα, and nitric oxide synthase (iNOS), which exacerbate the neurotoxicity [ 140 , 142 , 143 ]. Microglia can also be “alternatively” activated and release anti-inflammatory factors such as IL-10, transforming growth factor ß (TGFβ), and cluster differentiation 206 (CD206), which are neuroprotective [ 139 , 144 ]. Interestingly, microglia state is now well established as a continuum, rather than static states [ 145 ], hence modification of this population serves as possible avenue for altering NSCs.…”

Microglial Metamorphosis in Three Dimensions in Virus Limbic Encephalitis: An Unbiased Pictorial Representation Based on a Stereological Sampling Approach of Surveillant and Reactive Microglia

“…Although microglia under homeostatic conditions have delicate, branching extensions oriented radially from a small elliptical soma [84,86], they exhibit a variety of forms that can undergo forward and reverse morphofunctional changes, supporting distinct neuroimmune functions in both homeostatic and non-homeostatic conditions [66,[86][87][88][89]. Indeed, in almost all brain diseases, pathological progression is influenced by microglial cells [84] that react with the development of multiple morphofunctional phenotypes [90,91] as a function of age, environment (e.g., lifestyle), and the nature of the insult [92]. The multivariate statistical analysis of morphometric features of 3D-reconstructed microglia from homeostatic (control) and non-homeostatic (Piry virus-infected) mice in the current work revealed a kaleidoscope of microglial morphologies.…”