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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 199 records · Page 11
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Genetically engineered mouse models of esophageal cancer

Esophageal cancer is the most common cause of cancer-related death worldwide with a diverse geographical distribution, poor prognosis, and diagnosis in advanced stages of the disease. Identification of the mechanisms involved in esophageal cancer development is evaluative to improve outcomes for patients. Genetically engineered mouse models (GEMMs) of cancer provide the physiologic, molecular, and histologic features of the human tumors to determine the pathogenesis and treatments for cancer, hence exhibiting a source of tremendous potential for oncology research. The advancement of cancer modeling in mice has improved to the extent that researchers can observe and manipulate the disease process in a specific manner. Despite the significant differences between mice and humans, mice can be great models for human oncology researches due to similarities between them at the molecular and physiological levels. Due to most of the existing esophageal cancer GEMMs do not propose an ideal system for pathogenesis of the disease, genetic risks, and microenvironment exposure, so identification of challenges in GEM modeling and well-developed technologies are required to obtain the most value for patients. In this review, we describe the biology of human and mouse, followed by the exciting esophageal cancer mouse models with a discussion of applicability and challenges of these models for generating new GEMMs in future studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Whole-Genome Sequences of Thirteen Isolates of Borrelia burgdorferi

Borrelia burgdorferi is a causative agent of Lyme disease in North America and Eurasia. The first complete genome sequence of B. burgdorferi strain 31, available for more than a decade, has assisted research on the pathogenesis of Lyme disease. Because a single genome sequence is not sufficient to understand the relationship between genotypic and geographic variation and disease phenotype, we determined the whole-genome sequences of 13 additional B. burgdorferi isolates that span the range of natural variation. These sequences should allow improved understanding of pathogenesis and provide a foundation for novel detection, diagnosis, and prevention strategies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2010

Mutations Abrogating VP35 Interaction with Double-Stranded RNA Render Ebola Virus Avirulent in Guinea Pigs

Ebola virus (EBOV) protein VP35 is a double-stranded RNA (dsRNA) binding inhibitor of host interferon (IFN)-{alpha}/{beta} responses that also functions as a viral polymerase cofactor. Recent structural studies identified key features, including a central basic patch, required for VP35 dsRNA binding activity. To address the functional significance of these VP35 structural features for EBOV replication and pathogenesis, two point mutations, K319A/R322A, that abrogate VP35 dsRNA binding activity and severely impair its suppression of IFN-{alpha}/{beta} production were identified. Solution nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography reveal minimal structural perturbations in the K319A/R322A VP35 double mutant and suggest that loss of basic charge leads to altered function. Recombinant EBOVs encoding the mutant VP35 exhibit, relative to wild-type VP35 viruses, minimal growth attenuation in IFN-defective Vero cells but severe impairment in IFN-competent cells. In guinea pigs, the VP35 mutant virus revealed a complete loss of virulence. Strikingly, the VP35 mutant virus effectively immunized animals against subsequent wild-type EBOV challenge. These in vivo studies, using recombinant EBOV viruses, combined with the accompanying biochemical and structural analyses directly correlate VP35 dsRNA binding and IFN inhibition functions with viral pathogenesis. Moreover, these studies provide a framework for the development of antivirals targeting this critical EBOV virulence factor.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Indole-3-acetaldehyde dehydrogenase-dependent auxin synthesis contributes to virulence of Pseudomonas syringae strain DC3000

The bacterial pathogen Pseudomonas syringae modulates plant hormone signaling to promote infection and disease development. P. syringae uses several strategies to manipulate auxin physiology in Arabidopsis thaliana to promote pathogenesis, including its synthesis of indole-3-acetic acid (IAA), the predominant form of auxin in plants, and production of virulence factors that alter auxin responses in the host; however, the role of pathogen-derived auxin in P. syringae pathogenesis is not well understood. Here we demonstrate that P. syringae strain DC3000 produces IAA via a previously uncharacterized pathway and identify a novel indole-3-acetaldehyde dehydrogenase, AldA, that functions in IAA biosynthesis by catalyzing the NAD-dependent formation of IAA from indole-3-acetaldehyde (IAAld). Biochemical analysis and solving of the 1.9 Å resolution x-ray crystal structure reveal key features of AldA for IAA synthesis, including the molecular basis of substrate specificity. Disruption of aldA and a close homolog, aldB, lead to reduced IAA production in culture and reduced virulence on A. thaliana. We use these mutants to explore the mechanism by which pathogen-derived auxin contributes to virulence and show that IAA produced by DC3000 suppresses salicylic acid-mediated defenses in A. thaliana. Thus, auxin is a DC3000 virulence factor that promotes pathogenicity by suppressing host defenses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Assessing the Dynamics and Complexity of Disease Pathogenicity Using 4-Dimensional Immunological Data

Investigating disease pathogenesis and personalized prognostics are major biomedical needs. Because patients sharing the same diagnosis can experience different outcomes, such as survival or death, physicians need new personalized tools, including those that rapidly differentiate several inflammatory phases. To address these topics, a pattern recognition-based method (PRM) that follows an inverse problem approach was designed to assess, in <10 min, eight concepts: synergy , pleiotropy , complexity , dynamics , ambiguity , circularity , personalized outcomes , and explanatory prognostics (pathogenesis). By creating thousands of secondary combinations derived from blood leukocyte data, the PRM measures synergic, pleiotropic, complex and dynamic data interactions, which provide personalized prognostics while some undesirable features—such as false results and the ambiguity associated with data circularity-are prevented. Here, this method is compared to Principal Component Analysis (PCA) and evaluated with data collected from hantavirus-infected humans and birds that appeared to be healthy. When human data were examined, the PRM predicted 96.9 % of all surviving patients while PCA did not distinguish outcomes. Demonstrating applications in personalized prognosis, eight PRM data structures sufficed to identify all but one of the survivors. Dynamic data patterns also distinguished survivors from non-survivors, as well as one subset of non-survivors, which exhibited chronic inflammation. When the PRM explored avian data, it differentiated immune profiles consistent with no, early, or late inflammation. Yet, PCA did not recognize patterns in avian data. Findings support the notion that immune responses, while variable, are rather deterministic: a low number of complex and dynamic data combinations may be enough to, rapidly, unmask conditions that are neither directly observable nor reliably forecasted.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Technologies and Approaches to Elucidate and Model the Virulence Program of Salmonella.

Salmonella is a primary cause of enteric diseases in a variety of animals. During its evolution into a pathogenic bacterium, Salmonella acquired an elaborate regulatory network that responds to multiple environmental stimuli within host animals and integrates them resulting in fine regulation of the virulence program. The coordinated action by this regulatory network involves numerous virulence regulators, necessitating genome-wide profiling analysis to assess and combine efforts from multiple regulons. In this review we discuss recent high-throughput analytic approaches to understand the regulatory network of Salmonella that controls virulence processes. Application of high-throughput analyses have generated a large amount of data and driven development of computational approaches required for data integration. Therefore, we also cover computer-aided network analyses to infer regulatory networks, and demonstrate how genome-scale data can be used to construct regulatory and metabolic systems models of Salmonella pathogenesis. Genes that are coordinately controlled by multiple virulence regulators under infectious conditions are more likely to be important for pathogenesis. Thus, reconstructing the global regulatory network during infection or, at the very least, under conditions that mimic the host cellular environment not only provides a bird’s eye view of Salmonella survival strategy in response to hostile host environments but also serves as an efficient means to identify novel virulence factors that are essential for Salmonella to accomplish systemic infection in the host.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Structural insights into glutathione-mediated activation of the master regulator PrfA in Listeria monocytogenes

Listeria monocytogenes is a Gram-positive and facultative intracellular bacterial pathogen with two distinct lifestyles: saprophytic in the soil and parasitic in host cells. L. monocytogenes can cause a foodborne infection characterized by bacteremia, meningoencephalitis, abortion or neonatal sepsis and a high case-fatality rate. In relation to pathogenesis, the expression of most virulence genes in L. monocytogenes is regulated by the master regulator PrfA, which is a member of the Crp/Fnr family of site-specific DNA-binding transcription regulators. The absolute requirement of PrfA for pathogenesis was shown utilizing L. monocytogenes strains with deletions or loss-of-function mutations within the prfA gene. PrfA activates transcription by binding to a palindromic promoter element termed the PrfA box (tTAACanntGTtAa). Very recently, glutathione (GSH), either generated by bacteria or derived from host cells, was found to be the essential small molecule cofactor of PrfA through allosteric binding to the protein. PrfA G145S , the most well studied constitutively active mutant, was found to be able to completely bypass the requirement for glutathione during infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Mouse models of Ebola virus tolerance and lethality: characterization of CD-1 mice infected with wild-type, guinea pig-adapted, or mouse-adapted virus

Development of lethal models of Ebola virus disease has been achieved by the serial passage of virus isolates from human cases in mice and guinea pigs. Use of mice infected with non-adapted virus has been limited due to the absence of overt clinical disease. In recent years, newly recognized sequelae identified in human cases has highlighted the importance of continued investigations of non-lethal infection both in humans and animal models. Here, we revisit the use of rodent-adapted and non-adapted Ebola virus (EBOV) in mice to investigate infection tolerance and future utility of these models in pathogenesis and therapeutic intervention studies. We found that like non-adapted wild-type EBOV, guinea pig-adapted EBOV resulted in widespread tissue infection, variably associated with tissue pathology, and alterations in clinical and immunological analytes in the absence of overt disease. Notably, infection with either non-lethal variant did not greatly differ from lethal mouse-adapted EBOV until near the time end-point criteria are reached in these mice. Furthermore, these data support future investigations of pathogenesis, convalescence, and sequelae in mouse models of virus tolerance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency

Triosephosphate isomerase (TPI) is a glycolytic enzyme which homodimerizes for full catalytic activity. Mutations of the TPI gene elicit a disease known as TPI Deficiency, a glycolytic enzymopathy noted for its unique severity of neurological symptoms. Evidence suggests that TPI Deficiency pathogenesis may be due to conformational changes of the protein, likely affecting dimerization and protein stability. In this report, we genetically and physically characterize a human disease-associated TPI mutation caused by an I170V substitution. Human TPI I170V elicits behavioral abnormalities in Drosophila . An examination of hTPI I170V enzyme kinetics revealed this substitution reduced catalytic turnover, while assessments of thermal stability demonstrated an increase in enzyme stability. Furthermore, the crystal structure of the homodimeric I170V mutant reveals changes in the geometry of critical residues within the catalytic pocket. In the end, collectively these data reveal new observations of the structural and kinetic determinants of TPI deficiency pathology, providing new insights into disease pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

Both core and F proteins of hepatitis C virus could enhance cell proliferation in transgenic mice

Highlights: •HCV core and F proteins could induce hepatocyte proliferation in the transgenic mice. •β-Catenin signaling pathway was activated by core protein in the transgenic mice. •β-Catenin signaling pathway was activated by myc-F protein in the transgenic mice. •Expression of SMA protein was enhanced by core but not myc-F protein. -- Abstract: The role of the protein encoded by the alternative open reading frame (ARF/F/core+1) of the Hepatitis C virus (HCV) genome in viral pathogenesis remains unknown. The different forms of ARF/F/core+1 protein were labile in cultured cells, a myc-tag fused at the N-terminus of the F protein made it more stable. To determine the role of core and F proteins in HCV pathogenesis, transgenic mice with either protein expression under the control of Albumin promoter were generated. Expression of core protein and F protein with myc tag (myc-F) could be detected by Western blotting analysis in the livers of these mice. The ratio of liver to body weight is increased for both core and myc-F transgenic mice compared to that of wild type mice. Indeed, the proliferating cell nuclear antigen protein, a proliferation marker, was up-regulated in the transgenic mice with core or myc-F protein. Further analyses by microarray and Western blotting suggested that β-catenin signaling pathway was activated by either core or myc-F protein in the transgenic mice. These transgenic mice were further treated with either Diethynitrosamine (a tumor initiator) or Phenobarbital (a tumor promoter). Phenobarbital but not Diethynitrosamine treatment could increase the liver/body weight ratio of these mice. However, no tumor formation was observed in these mice. In conclusion, HCV core and myc-F proteins could induce hepatocyte proliferation in the transgenic mice possibly through β-catenin signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Lumican alleviates hypertrophic scarring by suppressing integrin-FAK signaling

Hypertrophic scarring (HS) is an overcompensation of wound healing that increases the risk of cosmetic disfigurement and functional impairment. No gold standard has been established for the treatment or prevention of HS. Our study aims to elucidate the expression and function of lumican in the pathogenesis of HS as well as the underlying mechanism involved in this procedure. An animal model of HS (rabbit ear) was established, and the Ad-lumican vectors were locally injected. Primary fibroblasts isolated from patients with hypertrophic burn scars were used in vitro. Histological and molecular changes in HS pathogenesis were evaluated. The results showed that lumican is significantly reduced in HS tissues and fibroblasts from HS patients as compared to normal skin or cells. Lumican levels were further suppressed in response to TGF-β stimulation. However, lumican upregulation effectively thinned the scar area and inhibited fibroblast proliferation and the cell cycle. Meanwhile, Ad-lumican administration suppressed the deposition of extracellular matrix, such as collagen and CTGF. Ad-lumican injected animals or fibroblasts presented comparable integrin α{sub 2}β{sub 1} expression while greatly reduced phosphorylation of FAK compared to the negative control. Moreover, Ad-lumican administration largely enhanced the binding of lumican to integrin α{sub 2}β{sub 1} and may thus inhibit the signaling propagation of collagen-integrin α{sub 2}β{sub 1}. Overall, the restoration of lumican levels contributed to suppressing the HS progression by inhibiting collagen-integrin α{sub 2}β{sub 1}-FAK signaling. - Highlights: • Lumican is downregulated during hypertrophic scar formation. • Lumican inhibits fibroblast proliferation. • Lumican inhibits extracellular matrix deposition. • Lumican suppresses collagen-integrin-FAK signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Imbalance of mitochondrial dynamics in Drosophila models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease, characterized by progressive and selective loss of motor neurons in the brain and spinal cord. DNA/RNA-binding proteins such as TDP-43, FUS, and TAF15 have been linked with the sporadic and familial forms of ALS. However, the exact pathogenic mechanism of ALS is still unknown. Recently, we found that ALS-causing genes such as TDP-43, FUS, and TAF15 genetically interact with mitochondrial dynamics regulatory genes. In this study, we show that mitochondrial fission was highly enhanced in muscles and motor neurons of TDP-43, FUS, and TAF15-induced fly models of ALS. Furthermore, the mitochondrial fission defects were rescued by co-expression of mitochondrial dynamics regulatory genes such as Marf, Opa1, and the dominant negative mutant form of Drp1. Moreover, we found that the expression level of Marf was decreased in ALS-induced flies. These results indicate that the imbalance of mitochondrial dynamics caused by instability of Marf is linked to the pathogenesis of TDP-43, FUS, and TAF15-associated ALS. - Highlights: • Mitochondrial fission is highly enhanced in TDP-43, FUS, and TAF15-induced fly models of ALS. • Excessive mitochondrial fragmentation in fly models of ALS is restored by mitochondrial dynamics regulatory genes. • Level of Marf protein is decreased in TDP-43, FUS, and TAF15-mediated ALS. • Imbalance of mitochondrial dynamics caused by Marf instability is linked to the pathogenesis of ALS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin

Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis. - Highlights: • Suggesting a new mechanism of insulin-triggered VSMC functions. • Providing a new therapeutic strategies that target atherosclerosis in T2DM patients. • Providing a new strategies that target in-stent restenosis in T2DM patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tumor suppressive role of miR-1224-5p in keloid proliferation, apoptosis and invasion via the TGF-β1/Smad3 signaling pathway

The molecular mechanism of the pathogenesis of keloids is still not known and the clinical management of keloids remains challenging. MiRNA (microRNA) is a novel class of small regulatory RNAs that has emerged as key post-transcriptional regulators of gene expression. MiRNAs participate in diverse biological processes of various skin diseases and function as key regulators in the occurrence and development of tumors. The purpose of this study was to investigate the involvement of miRNAs in keloid pathogenesis. We performed miRNA microarray analysis to compare miRNA expression between keloid and normal skin samples. We found that 46 miRNAs were upregulated and 28 miRNAs were downregulated in keloid compared with normal skin samples. We focused on miR-1224-5p, which has been reported to function in cancers, although the expression and mechanism of miR-1224-5p in keloids remain to be explored. Overexpression of miR-1224-5p led to inhibition of keloid fibroblast proliferation, promotion of apoptosis and decrease of migration and invasion. Our results suggest that downregulation of miR-1224-5p may be one of the mechanisms involved in the occurrence and development of keloids.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Overexpression of microRNA-26a protects against deficient β-cell function via targeting phosphatase with tensin homology in mouse models of type 2 diabetes

The prevalence of type 2 diabetes mellitus (T2DM) increased rapidly in the world. The development of β-cell dysfunction is the quintessential defects in T2DM patients However, the pathogenesis of β-cell dysfunction is still unclear. MicroRNAs are short non-coding RNAs and has been reported to be involved in pathogenesis of β-cell dysfunction and T2DM. Here, we investigated the mechanisms by which miR-26a regulate β-cell function and insulin signaling pathway in high fat diet (HFD) fed and db/db T2DM mice model. The expression of miR-26a was down-regulated dramatically in the serum and islets of both HFD and db/db mice model. miR-26a overexpression protected against HFD-induced diabetes and maintained prolonged normoglycemic time in HFD fed mice. Overexpression of miR-26a improved β-cell dysfunction in T2DM mice. Further, we identified that PTEN is a direct target gene of miR-26a. Overexpression of miR-26a significantly inhibited the luciferase activity of hPTEN 3′-UTR, while the effect of miR-26a disappeared when the miR-26a potential binding site within the PTEN 3′-UTR was mutated. Overexpression of miR-26a reduced both the mRNA and protein levels of PTEN in vitro and in vivo. We also found that miR-26a overexpression increased the expression of p-Akt and p-FoxO-1, while the effect of miR-26a was blocked by PTEN overexpression. In conclusion, our data indicated that miR-26a potentially contributes to the β-cell dysfunction in T2DM, and miR-26a may be a new therapeutic strategy against T2DM.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

B cell activation in the cecal patches during the development of an experimental colitis model

Highlights: • Cecal patch (CP) ulcerations are seen in the oxazolone colitis model. • Th1, Th2 and Th17 responses in the colon are induced by oxazolone treatment. • Appendectomy attenuates colitis along with decrease in these Th responses. • Colitis and CP ulcerations are also attenuated by the absence of mature B cells. • Intravital imaging shows B cell activation in CP in the setting of colitis. Although previous studies have suggested that appendix seems to be involved in the colitis, the role of this in the pathogenesis remains unclear. In this study, we assessed the importance of appendiceal lymphoid follicles, specifically the cecal patches (CP) in mice, using an experimental colitis model. Treatment with oxazolone resulted in ulcerations particularly at CP with follicular expansion as well as colitis. The colitis was attenuated by either appendectomy or the absence of mature B cells. We therefore established an intravital imaging system accompanied by the fluorescence resonance energy transfer technology to analyze the dynamic immune response of CP B cells. Our observation revealed frequent Ca{sup 2+} signaling in CP B cells during the early phase of colitis development. These findings suggested that the CP B cells may be involved in the pathogenesis of colitis including inflammatory bowel diseases in humans.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A novel circular RNA, hsa{sub c}irc{sub 0}046701, promotes carcinogenesis by increasing the expression of miR-142-3p target ITGB8 in glioma

Highlights: • We identified a novel circular RNA, hsa{sub c}irc{sub 0}046701 in glioma cells. • Hsa{sub c}irc{sub 0}046701 was significantly upregulated in glioma tissues. • Hsa{sub c}irc{sub 0}046701 sponges miR-142-3p in glioma. • MiR-142-3p directly targets ITGB8 in glioma. • Hsa{sub c}irc{sub 0}046701/miR-142-3p/ITGB8 axis plays critical roles in glioma pathogenesis. In the present study, we identified a novel circular RNA (circRNA), hsa{sub c}irc{sub 0}046701, in glioma cells. We measured the expression of hsa{sub c}irc{sub 0}046701 using qRT-PCR in glioma tissues and cell lines, and explored its functions using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, and Transwell assays. Luciferase reporter assays were performed to validate the correlation between microRNA miR-142-3p and hsa{sub c}irc{sub 0}046701 or integrin subunit beta 8 (ITGB8). The results showed that hsa{sub c}irc{sub 0}046701 was significantly upregulated in glioma tissues and cell lines, and knockdown of hsa{sub c}irc{sub 0}046701 inhibited cell proliferation and invasion. Luciferase reporter assays indicated that hsa{sub c}irc{sub 0}046701 functions as a sponge for miR-142-3p and regulates the expression of ITGB8. Subsequently, functional assays revealed that silencing of hsa{sub c}irc{sub 0}046701 could upregulate miR-142-3p, resulting in downregulation of ITGB8. The results demonstrated that the hsa{sub c}irc{sub 0}046701/miR-142-3p/ITGB8 axis might play critical regulatory roles in the pathogenesis and development of glioma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease

Highlights: • TREM2, Arginase-1 and proinflammatory cytokines increased in the midbrain of PD mice. • Knockdown of TREM2 in BV2 microglia exaggerated M1 microglial inflammatory responses. • TREM2 overexpression promoted M2 polarization and alleviated microglial inflammation. • TREM2 plays a crucial role in altering M1 microglia to M2 phenotype. Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain. Emerging evidence indicates that TREM2 enhances the phagocytosis function of microglia and suppress inflammation. Based on these evidence, we hypothesized that TREM2 might play a protective role through regulating microglia polarization. Here, we employ a lentiviral strategy to overexpress or suppress TREM2 on microglia and found that TREM2 was essential for M2 microglia polarization. Knockdown of TREM2 in BV2 microglia inhibited M2 polarization and lead to exaggeration of M1 microglial inflammatory responses, whereas overexpression of TREM2 promoted M2 polarization and alleviated microglial inflammation. We also observed that the TREM2 level was higher in the midbrain of PD mice, which was accompanied by an elevated level of Arginase-1 and increased proinflammatory cytokines, suggesting that TREM2 is an important factor in switching the microglia phenotypes. Taken together, these findings indicate that TREM2 plays a crucial role in altering the proinflammatory M1 microglia to M2 phenotype and has beneficial effects in the immune pathogenesis of PD.

60 APPLIED LIFE SCIENCES↗