Lai Guan Ng

Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.

Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.

Tissue macrophages have a split personality Resident tissue macrophages (RTMs) reside in various tissue-specific niches during development. They evince microenvironment-directed phenotypes that support host defense and tissue homeostasis. Chakarov et al. used single-cell RNA sequencing and fate-mapping of murine lung RTMs to interrogate RTM-subset heterogeneity, interrelationships, and ontogeny (see the Perspective by Mildner and Yona). In addition to alveolar macrophages, they identified two different interstitial macrophage populations. One population mostly abutted nerve fibers; the other population preferentially localized near blood vessels and appeared to support vessel integrity and inhibit inflammatory cell infiltration into tissues. Science , this issue p. eaau0964 ; see also p. 1154