Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches

Abstract

Background The immune cell compartment of the mammalian brain changes dramatically and peripheral T cells infiltrate the brain parenchyma during normal aging. However, the mechanisms underlying age-related T cell infiltration in the central nervous system remain unclear. Results Chronic inflammation and peripheral T cell infiltration were observed in the subventricular zone of aged mice. Cell-cell interaction analysis revealed that aged microglia released CCL3 to recruit peripheral CD8+ memory T cells. Moreover, the aged microglia shifted towards a pro-inflammation state and released TNF-α to upregulate the expression of VCAM1 and ICAM1 in brain venous endothelial cells, which promoted the transendothelial migration of peripheral T cells. In vitro experiment reveals that human microglia would also transit to a chemotactic phenotype when treated with CSF from the elderly. Conclusions Our research demonstrated that microglia play an important role in the aging process of brain by shifting towards a pro-inflammation and chemotactic state. Aged microglia promote T cell infiltration by releasing chemokines and upregulating adhesion molecules on venous brain endothelial cells.

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

“…The data on T-cell infiltration into the parenchyma with non-pathological aging is varied with reports ranging from no or limited infiltration to significant numbers [89][90][91] . While this question remains to be definitively answered, microglial reactivation could serve to recruit T-cells 92 and microglial proximity to pericytes and endothelial cells suggest they could present MHC-I to infiltrating T-cells 93 . In turn, T-cells could modulate microglial phenotype 94 .…”

Syk inhibitors protect against microglia-mediated neuronal loss in culture

“…Microglia are resident macrophages of the central nervous system (CNS) and are increasingly implicated in brain pathologies such as Alzheimer’s disease (AD), Parkinson’s disease, stroke, brain trauma, schizophrenia, autism, retinal and spinal pathology, as well as brain ageing ( Colonna and Butovsky, 2017 ; Qin et al, 2019 ; Greenhalgh et al, 2020 ; Kwon and Koh, 2020 ; Blaylock and Faria, 2021 ). These dynamic cells carry out disease-modifying functions, including: phagocytosis, degradation, and compaction of amyloid plaques ( Fu et al, 2012 ; Condello et al, 2015 ; Yuan et al, 2016 ; Feng et al, 2020 ; Huang et al, 2021 ; Lemke and Huang, 2022 ); regulation of inflammatory states ( Heneka et al, 2013 ); phagocytosis of synapses ( Stevens et al, 2007 ; Schafer et al, 2012 ; Hong et al, 2016 ); phagocytosis of dead cells and debris ( Sierra et al, 2010 ; Anderson et al, 2022 ); phagocytosis of stressed neurons ( Fricker et al, 2012a , b ); and recruiting peripheral immune cells to the brain ( Zhang et al, 2022 ). Thus, it is important to better understand the intracellular signalling pathways controlling these contrasting functions of microglia.…”

A dual hit of α-synuclein internalization and immune challenge leads to the formation and maintenance of Lewy body-like inclusions in human dopaminergic neurons

“…In addition to microglia, we believe that neuronal exposure to IFN-γ may also occur through immune cell secretions, following their infiltration into the brain 45 , as immune cells are robust producers and secretors of IFN-γ 81 . In fact, aging microglia have been shown to facilitate immune system infiltration into the brain 85 . Exposure to IFN-γ can induce antigen presentation in neurons 81 , which may lead neurons to be further vulnerable to the immune system via autoimmune-mediated mechanisms 86 , and perhaps more likely to form inclusions as a response to α-syn upregulation and oxidative stress 87, 88 .…”