Amanda Sierra1,2,3, Veronique E. Miron4,5,6, Rosa C. Paolicelli7 and Richard M. Ransohoff8 1Achucarro Basque Center for Neuroscience, Glial Cell Biology Laboratory, Science Park of UPV/EHU, E-48940 Leioa, Bizkaia, Spain 2Department of Biochemistry and Molecular Biology, University of the Basque Country EHU/UPV, 48940 Leioa, Spain 3Ikerbasque Foundation, Bilbao 48009, Spain 4BARLO Multiple Sclerosis Centre, Keenan Research Centre for Biomedical Science at St. Michael's Hospital, Toronto M5B 1T8, Canada 5Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada 6UK Dementia Research Institute at the University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4TJ, United Kingdom 7Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, CH-1005 Lausanne, Switzerland 8Third Rock Ventures, Boston, Massachusetts 02215, USA Correspondence: amanda.sierraachucarro.org; rransohoffthirdrockventures.com

Microglia are usually referred to as “the innate immune cells of the brain,” “the resident macrophages of the central nervous system” (CNS), or “CNS parenchymal macrophages.” These labels allude to their inherent immune function, related to their macrophage lineage. However, beyond their classic innate immune responses, microglia also play physiological roles crucial for proper brain development and maintenance of adult brain homeostasis. Microglia sense both external and local stimuli through a variety of surface receptors. Thus, they might serve as integrative hubs at the interface between the external environment and the CNS, able to decode, filter, and buffer cues from outside, with the aim of preserving and maintaining brain homeostasis. In this perspective, we will cast a critical look at how these multiple microglial functions are acquired and coordinated, and we will speculate on their impact on human brain physiology and pathology.