Abstract
During postnatal development, microglia, the resident innate immune cells of the central nervous system are constantly monitoring the brain parenchyma, cleaning the cell debris, the synaptic contacts overproduced and also maintaining the brain homeostasis. In this context, the postnatal microglia need some control over the innate immune response. One such molecule recently described to be involved in modulation of immune response is TREM2 (triggering receptor expressed on myeloid cells 2). Although some studies have observed TREM2 mRNA in postnatal brain, the regional pattern of the TREM2 protein has not been described. We therefore characterized the distribution of TREM2 protein in mice brain from Postnatal day (P) 1 to 14 by immunostaining. In our study, TREM2 protein was expressed only in microglia/macrophages and is developmentally downregulated in a region-dependent manner. Its expression persisted in white matter, mainly in caudal corpus callosum, and the neurogenic subventricular zone for a longer time than in grey matter. Additionally, the phenotypes of the TREM2+ microglia also differ; expressing CD16/32, MHCII and CD86 (antigen presentation markers) and CD68 (phagocytic marker) in different regions as well as with different intensity till P7. The mannose receptor (CD206) colocalized with TREM2 only at P1–P3 in the subventricular zone and cingulum, while others persisted at low intensities till P7. Furthermore, the spatiotemporal expression pattern and characterization of TREM2 indicate towards its other plausible roles in phagocytosis, progenitor’s fate determination or microglia phenotype modulation during postnatal development. Hence, the increase of TREM2 observed in pathologies may recapitulate their function during postnatal development, as a better understanding of this period may open new pathway for future therapies.
Highlights
Microglia are the resident innate immune cells of the central nervous system (CNS), ontogenically related to macrophages and they derive from yolk sac to enter brain at early embryonic development [1,2]; migrating through the brain following a specific pattern [3]
Developmental downregulation of TREM2 was observed, showing a faster reduction in grey matter than in white matter, where it was detectable till P10, almost exclusively in cc (Fig. 1F)
While TREM2 protein was not detected in grey matter after P5, it was still expressed in corpus callosum at P10
Summary
Microglia are the resident innate immune cells of the central nervous system (CNS), ontogenically related to macrophages and they derive from yolk sac to enter brain at early embryonic development [1,2]; migrating through the brain following a specific pattern [3]. The postnatal microglia need to control the innate immune response in context to cellular death during development using endogenous mechanisms regulating inflammatory cell activation, including the expression of modulatory and/or inhibitory membrane receptors These receptors play a key role in the regulation of inflammatory processes, mainly by cell-cell interaction with neurons, such as CX3CR1-CX3CL1 [20], CD200R-CD200 [21,22,23], CD47-CD172a [24] and TREM2-HSP60 (as putative endogenous receptor) [25,26,27], among others
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