Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell‐cell interglial interaction

Abstract

Aging and neurodegenerative diseases share a condition of neuroinflammation entailing the production of endogenous cell debris in the CNS that must be removed by microglia (i.e., resident macrophages), to restore tissue homeostasis. In this context, extension of microglial cell branches toward cell debris underlies the mechanisms of microglial migration and phagocytosis. Amoeboid morphology and the consequent loss of microglial branch functionality characterizes dysregulated microglia. Microglial migration is assisted by another glial population, the astroglia, which forms a dense meshwork of cytoplasmic projections. Amoeboid microglia and disrupted astrocyte meshwork are consistent traits in aged CNS. In this study, we assessed a possible correlation between microglia and astroglia morphology in rat models of chronic neuroinflammation and aging, by 3‐dimensional confocal analysis implemented with particle analysis. Our findings suggest that a microglia‐astroglia interaction occurs in rat hippocampus via cell‐cell contacts, mediating microglial cell branching in the presence of inflammation. In aged rats, the impairment of such an interaction correlates with altered distribution, morphology, and inefficient clearance by microglia. These data support the idea that generally accepted functional boundaries between microglia and astrocytes should be re‐evaluated to better understand how their functions overlap and interact.—Lana, D., Ugolini, F., Wenk, G. L., Giovannini, M. G., Zecchi‐Orlandini, S., Nosi, D. Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell‐cell interglial interaction. FASEB J. 33, 4007–4020 (2019). http://www.fasebj.org

Neuroinflammatory processes are augmented in mice overexpressing human heat-shock protein B1 following ethanol-induced brain injury

“…For example, NFκB-mediated astrocytic expression of WNT induces microglia proliferation or the ATP released from astrocyte can act on the purinergic receptors of microglia with concomitant induction of Ca 2+ signaling and IL-1β containing vesicula formation [65][66][67][68]. Astrocytes can also mediate microglial function and distribution by secreting a plethora of inflammatory cytokines and chemokines or through direct cell-cell interactions [69][70][71]. Therefore, we hypothesize that elevated intracellular hHSPB1 levels in astrocytes remaining in microglial cultures could have an effect on the release of these factors, contributing to the increased microglial activation.…”

Microglia senescence occurs in both substantia nigra and ventral tegmental area

“…In addition to neurochemical interactions via ligands and receptors, direct contact sites between microglia and neurons likely mediate fast and precise communication although the exact nature of this crosstalk still needs to be elucidated. To measure the agedependent changes (or lack thereof ) in contact sites between microglia and dopamine neurons we used 3D binary masks reconstruction image analysis(Lana et al, 2019; Figure 7a). As shown inFigure 7b,c, contact sites between microglia and TH+ neurons significantly increase with aging.…”

Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale

“…It is known that neurodegenerative microglia exhibit unbranched ameboid shape [ 67 ], suggesting a low efficiency of their targeting mechanisms. Indeed, microglial targeting in the “find me” step involves dynamic modifications of their cytoplasmic processes ( Figure 1 B), which show increased branching towards target molecules, based on chemical as well as mechanical stimuli [ 2 , 33 ]. Accordingly, it has been demonstrated that in an aged brain, senescent microglia show decreased branching ( Figure 1 C) and migration rate [ 68 ].…”

“…Astrocytes are synergic players with microglia in the neuroinflammatory response, directly performing clearance of amyloid species from the CNS [ 26 , 27 ] and influencing microglial phagocytosis [ 1 , 2 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Nevertheless, it has been suggested that in chronic neuroinflammation the phenotype of astrocytes may also vary from anti-inflammatory, neuroprotective [ 35 , 36 , 37 ] to a pro-inflammatory neurodegenerative phenotype [ 35 , 36 , 37 ], which should be induced by pro-inflammatory reactive microglia [ 35 , 36 ].…”

“…Increasing knowledge of such sequential relationships is leading to relevant advances in the field of neurodegenerative diseases. However, this task is complicated by the intense molecular crosstalk linking these glial cells and the occurrence of close mechanical interactions that also plays a relevant role in these processes [ 33 ]. Accordingly, this review, rather than providing a description of astroglia–microglia interactions during inflammation, will attempt to contextualize these reciprocal influences, with the aim of discussing how they might affect, or be affected by, the whole system.…”