Microglia control small vessel calcification via TREM2

Abstract

Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, Pdgfbret/ret, to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification.

Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development

“…Previous analyses have shown that developmental loss of pericytes, as occurs in constitutive Pdgfb mutants including Pdgfb ret/ret and other adult-viable Pdgfb loss-of-function mouse models, has a number of different consequences for brain vascular structure and function. 9,10,[13][14][15]28,29 These include the formation of a sparser network of wider capillaries, the specific reduction in the expression of certain BBB transporters, upregulated endothelial expression of growth factors and pro-inflammatory molecules, activation of angiogenic sprouting, the occurrence of two distinct modes of BBB impairment, i.e. increased transcytosis and hotspot leakage via disturbed endothelial junctions, and the progressive formation of microvascular-associated calcifications in deep brain regions modeling the human genetic disease PFBC.…”

“…Presence of osteopontin (SPP1) has been noticed in small non-calcified vessel-associated nodules in Pdgfb ret/ret brain thalamus and midbrain regions. 28 While we could identify rare small SPP1 positive nodules associated with the vasculature in the thalamus (d) qPCR analysis on the endothelial cell genes Fgfbp1, Bmp6 and Angpt2 performed on freshly isolated brain microvascular fragments in young and old mice (for litter and n number see Supplementary Table 1). The genes of interest were normalized to endogenous Gapdh levels (DCq) and these are presented as arbitrary units (a.…”

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

“…However, several studies also have shown the disadvantage of microglia deletion in disease processes. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 led to aggravated vascular calcification ( Zarb et al, 2021 ), and accelerated prion disease ( Carroll et al, 2018 ). Although one study reported that microglia depletion by PLX3397 exacerbated seizure severity and excitotoxicity-induced neuronal degeneration ( Liu M. et al, 2020 ), other studies predicted CSF1R to be a potential target for anti-epileptic drugs ( Lyman and Chetkovich, 2019 ; Gerard et al, 2021 ) as CSF1R blockade attenuating epilepsy seizures has been validated in three pre-clinical models of epilepsy ( Srivastava et al, 2018 ).…”

Modulation of Sirt1-mTORC1 Pathway in Microglia Attenuates Retinal Ganglion Cell Loss After Optic Nerve Injury

“… 12 Besides immune activity, the microglia also participate in the development and maintenance of neural networks, as well as in neurovascular unit homeostasis. 7 , 13 , 14 Noteworthy, genetic ablation and/or pharmacological blockade of microglia shows neuroprotective effect in neurodegenerative diseases. 15 , 16 …”

“…12 Besides immune activity, the microglia also participate in the development and maintenance of neural networks, as well as in neurovascular unit homeostasis. 7,13,14 Noteworthy, genetic ablation and/or pharmacological blockade of microglia shows neuroprotective effect in neurodegenerative diseases. 15,16 Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, deacetylates transcription factors, signaling molecules, and histones.…”