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Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

Many serine proteinase inhibitors of the serpin superfamily have evolved in vertebrates and invertebrates to regulate serine proteinase cascades that mediate the host defense responses. We have isolated an immuneresponsive serpin from the tobacco hornworm, Manduca sexta. This inhibitor, M. sexta serpin-3, contains a reactive site loop strikingly similar to the proteolytic activation site in prophenoloxidase (pro-PO). Molecular cloning and sequence comparison indicate that serpin-3 is orthologous to Drosophila melanogaster serpin 27A, a regulator of melanization. M. sexta serpin-3 is constitutively present in hemolymph at a low concentration of 5-12 g/ml and increases to 30 -75 g/ml after a microbial challenge. Recombinant serpin-3 efficiently blocks pro-PO activation in the hemolymph, and it forms SDS-stable acyl-enzyme complexes with purified pro-PO-activating proteinases (PAPs) from M. sexta. PAP-serpin-3 complexes were isolated by immunoaffinity chromatography from hemolymph activated by treatment with Micrococcus luteus. Kinetic analysis of PAP-serpin-3 association strongly suggests that serpin-3 is a physiological regulator of the pro-PO activation reaction.

A critical challenge for chemotherapy is the development of chemoresistance in breast cancer. However, the underlying mechanisms and validated predictors remain unclear. Extracellular vesicles (EVs) have gained attention as potential means for cancer cells to share intracellular contents. In adriamycin-resistant human breast cancer cells (MCF-7/ADM), we analyzed the role of transient receptor potential channel 5 (TrpC5) in EV formation and transfer as well as the diagnostic implications. Up-regulated TrpC5, accumulated in EVs, is responsible for EV formation and trapping of adriamycin (ADM) in EVs. EV-mediated intercellular transfer of TrpC5 allowed recipient cells to acquire TrpC5, consequently stimulating multidrug efflux transporter P-glycoprotein production through a Ca 2+ -and activated T-cells isoform c3-mediated mechanism and thus, conferring chemoresistance on nonresistant cells. TrpC5-containing circulating EVs were detected in nude mice bearing MCF-7/ ADM tumor xenografts, and the level was lower after TrpC5-siRNA treatment. In breast cancer patients who underwent chemotherapy, TrpC5 expression in the tumor was significantly higher in patients with progressive or stable disease than in patients with a partial or complete response. TrpC5-containing circulating EVs were found in peripheral blood from patients who underwent chemotherapy but not patients without chemotherapy. Taken together, we found that TrpC5-containing circulating EVs may transfer chemoresistance property to nonchemoresistant recipient cells. It may be worthwhile to further explore the potential of using TrpC5-containing EVs as a diagnostic biomarker for chemoresistant breast cancer.T he development of chemotherapeutic resistance in breast cancer is a serious problem (1, 2). To date, the mechanisms underlying chemoresistance are still largely unknown, and no validated predictive factor of chemoresistance is available in the clinic. Therefore, it is important to identify the signaling pathways and search for circulating markers in breast cancer resistant to chemotherapy.The extracellular environment contains a large number of mobile membrane-limited vesicles named extracellular vesicles (EVs). Major EV populations include exosomes, microvesicles, and apoptotic bodies (1, 3-5). These dynamic EVs may have essential function in intercellular communication and immune regulation (5). Tumor cells also generate EVs (3, 4). Large quantities of tumor-derived circulating EVs have been found in the blood of patients with glioblastoma multiforme (4), pancreatic cancer (6), gastric cancer (7), and acute myeloid leukemia (8). They contain cell surface proteins, RNA, and DNA (3, 4, 9, 10). They mediate intercellular cross-talk by transferring their intravesicular contents from donor to recipient cells and participating in tumor invasion and metastasis (11-13). However, how these structures are generated and their importance in chemotherapeutic resistance in breast cancer are poorly understood.On the basis of our previous finding that transient receptor...

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Background: Resistance to 5-fluorouracil leads to the failure of chemotherapy for colorectal cancer. Results: Suppressing TrpC5 expression decreased nuclear ␤-catenin accumulation, reduced the induction of ABCB1, and reversed 5-fluorouracil resistance. Conclusion: TrpC5 is essential in ABCB1 induction and drug resistance in human colorectal cancer cells. Significance: These findings may help develop a novel target for overcoming resistance to chemotherapy in colorectal cancer.

Insect C-type lectins function as pattern recognition receptors in innate immunity. In the tobacco hornworm Manduca sexta, we have previously isolated three C-type lectins named immulectins, which are involved in innate immune responses. Here, we report a new member of the immulectin family, immulectin-4 (IML-4). IML-4 mRNA was detected in the fat body of control larvae and was induced in the fat body when larvae were injected with bacteria. Recombinant IML-4 bound to bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and the binding activity was not affected by addition of calcium or EGTA. IML-4 agglutinated bacteria and yeast, and agglutination of Escherichia coli by IML-4 was concentration- and calcium-dependent. IML-4 also enhanced haemocyte encapsulation and melanization.