Zhong et al. describe two novel roles for soluble TREM2 (sTREM2) in regulation of proinflammatory responses and prevention of cellular apoptosis in microglia.

BackgroundTREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined.MethodsPotential binding of oligomeric amyloid-β 1–42 (oAβ1–42) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ1–42 to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ1–42-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ1–42-bearing brain areas in vivo.ResultsWe found that oAβ1–42 bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ1–42. Furthermore, we identified several positively charged amino acids within residues 31–91 of TREM2 that were crucial for its interaction with oAβ1–42. Importantly, oAβ1–42 promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.ConclusionsOur data establish a critical link between oAβ1–42, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0247-7) contains supplementary material, which is available to authorized users.

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Necroptosis is a type of programmed necrosis regulated by receptor interacting protein kinase 1 (RIP1) and RIP3. Necroptosis is found to be accompanied by an overproduction of reactive oxygen species (ROS), but the role of ROS in regulation of necroptosis remains elusive. In this study, we investigated how shikonin, a necroptosis inducer for cancer cells, regulated the signaling leading to necroptosis in glinoma cells in vitro. Treatment with shikonin (2-10 μmol/L) dose-dependently triggered necrosis and induced overproduction of intracellular ROS in rat C6 and human SHG-44, U87 and U251 glioma cell lines. Moreover, shikonin treatment dose-dependently upregulated the levels of RIP1 and RIP3 and reinforced their interaction in the glioma cells. Pretreatment with the specific RIP1 inhibitor Nec-1 (100 μmol/L) or the specific RIP3 inhibitor GSK-872 (5 μmol/L) not only prevented shikonin-induced glioma cell necrosis but also significantly mitigated the levels of intracellular ROS and mitochondrial superoxide. Mitigation of ROS with MnTBAP (40 μmol/L), which was a cleaner of mitochondrial superoxide, attenuated shikonin-induced glioma cell necrosis, whereas increasing ROS levels with rotenone, which improved the mitochondrial generation of superoxide, significantly augmented shikonin-caused glioma cell necrosis. Furthermore, pretreatment with MnTBAP prevented the shikonin-induced upregulation of RIP1 and RIP3 expression and their interaction while pretreatment with rotenone reinforced these effects. These findings suggest that ROS is not only an executioner of shikonin-induced glioma cell necrosis but also a regulator of RIP1 and RIP3 expression and necrosome assembly.

The Lajishan ophiolite complex in the Qilian Orogen is one of several ophiolites situated between the Qaidam and North China blocks that record episodic closure of the Proto-Tethyan Ocean. Detailed field relations and geochemical and geochronological studies are critical to unraveling the tectonic processes responsible for an extensive period of intraoceanic subduction that produced juvenile ophiolite/island arc terranes, which were obducted onto continental margins during ocean closure. The Lajishankou ophiolite complex crops out along the northern margin of the South Qilian belt and was thrust over a Neoproterozoic-Ordovician passive margin sequence that was deposited upon the Proterozoic Central Qilian block. The mafic rocks in Lajishankou ophiolite complex are the most abundant slices and can be categorized into three distinct groups based on petrological, geochemical, and geochronological characteristics: massive island arc tholeiites, 509-Ma back-arc dolerite dykes, and 491-Ma pillow basaltic and dolerite slices that are of seamount origin in a back-arc basin. These results, together with spatial relationships, indicate that the Cambrian island arc rocks, ophiolite complex, and accretionary complex developed between 530 and 480 Ma as a single, intraoceanic arc-basin system as a result of south directed subduction of the Proto-Tethyan Ocean prior to Early Ordovician obduction of this system onto the Central Qilian block. Final continental amalgamation involved continental collision of the Central Qilian block with the Qaidam block during the Late Ordovician. This model solves the long-lasting discussion on the emplacement of the Lajishan ophiolite and contributes to an improved understanding of multiple accretionary and collisional processes in the Qilian Orogen.