Microglia Control Small Vessel Calcification Via TREM2

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Feb 27

PMID 33637522

Citations 22

Authors

Yvette Zarb

Sucheta Sridhar

Sina Nassiri

Sebastian Guido Utz

Johanna Schaffenrath

Upasana Maheshwari

Elisabeth J Rushing

K Peter R Nilsson

Mauro Delorenzi

Marco Colonna

Melanie Greter

Annika Keller

Affiliations

Soon will be listed here.

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, , 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.

Citing Articles

Targeting TREM2 signaling shows limited impact on cerebrovascular calcification.

Sridhar S, Zhou Y, Ibrahim A, Bertazzo S, Wyss T, Swain A Life Sci Alliance. 2024; 8(1).

PMID: 39467636 PMC: 11519321. DOI: 10.26508/lsa.202402796.

Transcriptional profiling in microglia across physiological and pathological states identifies a transcriptional module associated with neurodegeneration.

Guvenek A, Parikshak N, Zamolodchikov D, Gelfman S, Moscati A, Dobbyn L Commun Biol. 2024; 7(1):1168.

PMID: 39294270 PMC: 11411103. DOI: 10.1038/s42003-024-06684-7.

Methazolamide Can Treat Atherosclerosis by Increasing Immunosuppressive Cells and Decreasing Expressions of Genes Related to Proinflammation, Calcification, and Tissue Remodeling.

Zhou H, Zhang R, Li M, Wang F, Gao Y, Fang K J Immunol Res. 2024; 2024:5009637.

PMID: 39081633 PMC: 11288698. DOI: 10.1155/2024/5009637.

Osteopontin/SPP1: a potential mediator between immune cells and vascular calcification.

Zhao Y, Huang Z, Gao L, Ma H, Chang R Front Immunol. 2024; 15:1395596.

PMID: 38919629 PMC: 11196619. DOI: 10.3389/fimmu.2024.1395596.

Endothelial cells and macrophages as allies in the healthy and diseased brain.

Denes A, Hansen C, Oezorhan U, Figuerola S, de Vries H, Sorokin L Acta Neuropathol. 2024; 147(1):38.

PMID: 38347307 PMC: 10861611. DOI: 10.1007/s00401-024-02695-0.

References

Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M . Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003; 17(15):1835-40. PMC: 196228. DOI: 10.1101/gad.266803. View

Hagemeyer N, Hanft K, Akriditou M, Unger N, Park E, Stanley E . Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 2017; 134(3):441-458. PMC: 5951721. DOI: 10.1007/s00401-017-1747-1. View

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

Armulik A, Genove G, Mae M, Nisancioglu M, Wallgard E, Niaudet C . Pericytes regulate the blood-brain barrier. Nature. 2010; 468(7323):557-61. DOI: 10.1038/nature09522. View

Hickman S, Izzy S, Sen P, Morsett L, El Khoury J . Microglia in neurodegeneration. Nat Neurosci. 2018; 21(10):1359-1369. PMC: 6817969. DOI: 10.1038/s41593-018-0242-x. View

Iadecola C . The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron. 2017; 96(1):17-42. PMC: 5657612. DOI: 10.1016/j.neuron.2017.07.030. View

Friedman B, Srinivasan K, Ayalon G, Meilandt W, Lin H, Huntley M . Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep. 2018; 22(3):832-847. DOI: 10.1016/j.celrep.2017.12.066. View

Mann D . Calcification of the basal ganglia in Down's syndrome and Alzheimer's disease. Acta Neuropathol. 1988; 76(6):595-8. DOI: 10.1007/BF00689598. View

Thion M, Ginhoux F, Garel S . Microglia and early brain development: An intimate journey. Science. 2018; 362(6411):185-189. DOI: 10.1126/science.aat0474. View

10.

Maetzler W, Berg D, Funke C, Sandmann F, Stunitz H, Maetzler C . Progressive secondary neurodegeneration and microcalcification co-occur in osteopontin-deficient mice. Am J Pathol. 2010; 177(2):829-39. PMC: 2913375. DOI: 10.2353/ajpath.2010.090798. View

11.

Keller A, Westenberger A, Sobrido M, Garcia-Murias M, Domingo A, Sears R . Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013; 45(9):1077-82. DOI: 10.1038/ng.2723. View

12.

Li Q, Cheng Z, Zhou L, Darmanis S, Neff N, Okamoto J . Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron. 2019; 101(2):207-223.e10. PMC: 6336504. DOI: 10.1016/j.neuron.2018.12.006. View

13.

Hart A, Wyttenbach A, Perry V, Teeling J . Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun. 2011; 26(5):754-65. PMC: 3381227. DOI: 10.1016/j.bbi.2011.11.006. View

14.

Yona S, Kim K, Wolf Y, Mildner A, Varol D, Breker M . Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013; 38(1):79-91. PMC: 3908543. DOI: 10.1016/j.immuni.2012.12.001. View

15.

Fager N, Jaworski D . Differential spatial distribution and temporal regulation of tissue inhibitor of metalloproteinase mRNA expression during rat central nervous system development. Mech Dev. 2000; 98(1-2):105-9. DOI: 10.1016/s0925-4773(00)00437-8. View

16.

Hunter G, Kyle C, Goldberg H . Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem J. 1994; 300 ( Pt 3):723-8. PMC: 1138226. DOI: 10.1042/bj3000723. View

17.

Parkhurst C, Yang G, Ninan I, Savas J, Yates 3rd J, Lafaille J . Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013; 155(7):1596-609. PMC: 4033691. DOI: 10.1016/j.cell.2013.11.030. View

18.

Heneka M, Kummer M, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A . NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2012; 493(7434):674-8. PMC: 3812809. DOI: 10.1038/nature11729. View

19.

Pescatore L, Gamarra L, Liberman M . Multifaceted Mechanisms of Vascular Calcification in Aging. Arterioscler Thromb Vasc Biol. 2019; 39(7):1307-1316. DOI: 10.1161/ATVBAHA.118.311576. View

20.

Zarb Y, Weber-Stadlbauer U, Kirschenbaum D, Kindler D, Richetto J, Keller D . Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response. Brain. 2019; 142(4):885-902. PMC: 6439320. DOI: 10.1093/brain/awz032. View