Fig. 3

Probable ligand-induced TYROBP signaling in recruited microglia. Ligand-induced TYROBP signaling is initiated by apolipoprotein E, Aβ, debris, or other currently unidentified ligands at sensing receptors and leads to phosphorylation of the tyrosine residues in the cytoplasmic ITAM of TYROBP by SRC kinases and the recruitment of SYK. In turn, SYK signaling can increase transcription of Tyrobp and ApoE. This series of events forms the basis for the phenotypic switch from homeostatic microglia to DAM and may be in part post-transcriptionally regulated by miR-155. We speculate that in mice lacking Trem2, recruited microglia cause other receptor ectodomains to acquire sensing capability either because these receptors always signal by complexing with TYROBP, or because signals across other complexes are induced as a compensatory mechanism due to the absence of Trem2. Abbreviations: APOE, apolipoprotein E; C1q, complement protein C1q; Ccl6, C-C motif chemokine ligand 6; Cd52, CD52 molecule; Cd68, CD68 molecule; Clec7a, C-Type lectin domain containing 7A; Csf1, colony stimulating factor 1; Cst7, cystatin F; Ctsd, cathepsin D; Ctss, cathepsin S; Ctsz, cathepsin Z; DAM, disease-associated microglia; Hexb, hexosaminidase subunit beta; ITAM, immunoreceptor tyrosine-based activation motif; Itgax, integrin subunit alpha X; Itgb2, integrin subunit beta 2; Lyz2, lysozyme 2; miR-155, microRNA-155; SYK, spleen tyrosine kinase; TREM2, triggering receptor expressed on myeloid cells-2; TYROBP, tyrosine kinase binding protein; Y, tyrosine. Adapted and reprinted with permission from Wiley Publishing, Hoboken, NJ