Mononuclear phagocytes are key regulators of both tissue damage and repair in neuroinflammatory conditions such as multiple sclerosis. To examine divergent phagocyte phenotypes in the inflamed CNS, we introduce an in vivo imaging approach that allows us to temporally and spatially resolve the evolution of phagocyte polarization in a murine model of multiple sclerosis. We show that the initial proinflammatory polarization of phagocytes is established after spinal cord entry and critically depends on the compartment they enter. Guided by signals from the CNS environment, individual phagocytes then switch their phenotype as lesions move from expansion to resolution. Our study thus provides a real-time analysis of the temporospatial determinants and regulatory principles of phagocyte specification in the inflamed CNS.
Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs.
Highlights d The release of conventionally secreted cytokines is reduced in necroptotic cells d Receptor shedding occurs during TNF-induced necroptosis and apoptosis d Lysosomal components are released via lysosomal exocytosis during necroptosis
Sensing of nucleic acids by TLRs is crucial in the host defense against viruses and bacteria. Unc-93 homolog B1 (UNC93B1) regulates the trafficking of nucleic acid sensing TLRs from the ER to endolysosomes, where the TLRs encounter their respective ligands and become activated. Here we show that a carboxy-terminal tyrosine-based sorting motif (Yxx Φ) in UNC93B1 differentially regulates human nucleic acid sensing TLRs in a receptor- and ligand-specific manner. Destruction of the YxxΦ motif abolished TLR7, 8 and 9 activity towards nucleic acids in human B cells and monocytes, whereas TLR8 responses towards small molecules remained intact. The YxxΦ motif in UNC93B1 influenced the subcellular localization of human UNC93B1 via both adapter protein complex 1 (AP1)- and AP2-dependent trafficking pathways. However, loss of AP function was not causal for altered TLR responses, suggesting AP-independent functions of the YxxΦ motif in UNC93B1.
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