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Macropinosomes host TLR9 signaling and regulation of inflammatory responses in microglia

To support their innate immune and scavenging functions in the brain, microglia are equipped with Toll-like receptors (TLRs), including the intracellular receptor TLR9, which is activated by microbial CpG-rich DNA. Macropinocytosis is an abundant and inducible pathway in microglia for fluid-phase uptake and ingestion of microbes and cell debris. TLR9 signaling has been ascribed to endolysosomes, particularly lysosomes, which it accesses through direct transport or via internalization from the surface. Here, TLR9 and exogenous CpG-DNA are localized during uptake into fluid-filled macropinosomes, upon upregulated macropinocytosis, where acidic and proteolytic environments support MyD88-induced signaling. Macropinosomes represent an abundant pathway for endolysosomal traffic of TLR9 but are also a much more exposed site for nucleic acid activation of the receptor with a risk of excessive inflammation. To constrain TLR9 inflammation, macropinosomes also house the TLR9 co-receptor LRP1 and regulators Rab8a and PI3Kγ which augment Akt signaling and favor anti-inflammatory cytokine production. Macropinosomes and their inflammatory regulators are therefore important components of TLR9 pathways in microglia that are poised for surveillance and protection in the CNS.