Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7(−/−) fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.
Toll-like receptors (TLR) are key players of the innate and adaptive immune response in vertebrates. The original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis during development. Making use of real-time PCR, in situ hybridization, and immunohistochemistry we systematically examined the expression of TLR1–9 and the intracellular adaptor molecules MyD88 and TRIF during development of the mouse brain. Expression of TLR7 and TLR9 in the brain was strongly regulated during different embryonic, postnatal, and adult stages. In contrast, expression of TLR1–6, TLR8, MyD88, and TRIF mRNA displayed no significant changes in the different phases of brain development. Neurons of various brain regions including the neocortex and the hippocampus were identified as the main cell type expressing both TLR7 and TLR9 in the developing brain. Taken together, our data reveal specific expression patterns of distinct TLRs in the developing mouse brain and lay the foundation for further investigation of the pathophysiological significance of these receptors for developmental processes in the central nervous system of vertebrates.
Elucidating cellular mechanisms that maintain the intrahepatic immune balance is crucial to our understanding of viral or autoimmune liver diseases and allograft acceptance. Liver sinusoidal endothelial cells (LSECs) play an important role in modifying local immune responses to tolerance in major histocompatibility complex (MHC) I-restricted models, whereas their contribution in the MHCII context is still controversial. In an MHCII chimeric mouse model that excludes MHCII-mediated antigen presentation by professional antigen-presenting cells, we demonstrated that LSECs prime CD4 ؉ T cells to a CD45RB low memory phenotype lacking marker cytokine production for effector cells that was stable in vivo following immunogenic antigen re-encounter. Although these cells, which we term T LSEC , had the capacity to enter lymph nodes and the liver, they did not function as effector cells either in a delayed-type hypersensitivity reaction or in a hepatitis model. T LSEC inhibited the proliferation of naïve CD4 ؉ T cells in vitro although being CD25 low and lacking expression of forkhead box protein (FoxP)3. Furthermore, these cells suppressed hepatic inflammation as monitored by alanine aminotransferase levels and cellular infiltrates in a T cell-mediated autoimmune hepatitis model in vivo. Conclusion: T LSEC first described here might belong to the expanding group of FoxP3 ؊ regulatory T cells. Our findings strengthen the previously discussed assumption that CD4 ؉ T cell priming by nonprofessional antigen-presenting cells induces anti-inflammatory rather than proinflammatory phenotypes. Because recruitment of CD4 ؉ T cells is increased upon hepatic inflammation, T LSEC might contribute to shifting antigen-dependent immune responses to tolerance toward exogenous antigens or toward endogenous self-antigens, especially under inflammatory conditions. (HEPATOLOGY 2009;50:1904-1913 U nder physiological conditions, the liver seems rather to support the induction of peripheral tolerance than to establish immunity. 1 In particular, liver sinusoidal endothelial cells (LSECs) are believed to shift the hepatic immune balance toward tolerance by presenting major histocompatibility complex (MHC) Irestricted antigens, thereby inducing anergy and tolerance. 2,3 LSECs constitutively express MHCII and costimulatory molecules 4 and take up exogenous antigens. 2 Naïve CD4 ϩ T cells migrate into the liver 5,6 and interact with LSECs. 7 This raises the question whether LSECs also prime CD4 ϩ T cells. Coculturing naïve CD4 ϩ T cells with LSECs resulted in stimulation of the T cells. 8 Another recent study using LSEC preparations depleted of cells of hematopoietic origin has created doubts about the priming capacity of LSECs for naïve CD4 ϩ T cells in the absence of professional antigenpresenting cells (APCs). 9 Priming of naïve CD4 ϩ T cells by other nonprofessional APCs such as aortic endothelial cells or naïve B cells induces distinct T cell populations lacking cytokine production and displaying suppressive capaci-
MicroRNAs (miRNAs) are non-coding RNAs originally involved in RNA silencing and post-transcriptional regulation of gene expression. We have shown in previous work that the miRNA let-7b can act as a signalling molecule for Toll-like receptor 7, thereby initiating innate immune pathways and apoptosis in the central nervous system. Here, we investigated whether different members of the miRNA family let-7, abundantly expressed in the brain, are released into the human cerebrospinal fluid (CSF) and whether quantitative differences in let-7 copies exist in neurodegenerative diseases. RNA isolated from CSF of patients with Alzheimer´s disease (AD) and from control patients with frontotemporal lobe dementia (FTLD), major depressive episode (MDE) without clinical or neurobiological signs of AD, and healthy individuals, was reverse transcribed with primers against nine let-7 family members, and miRNAs were quantified and analyzed comparatively by quantitative PCR. let-7 miRNAs were present in CSF from patients with AD, FTLD, MDE, and healthy controls. However, the amount of individual let-7 miRNAs in the CSF varied substantially. CSF from AD patients contained higher amounts of let-7b and let-7e compared to healthy controls, while no differences were observed regarding the other let-7 miRNAs. No increase in let-7b and let-7e was detected in CSF from FTLD patients, while in CSF from MDE patients, let-7b and let-7e copy levels were elevated. In CSF from AD patients, let-7b and let-7e were associated with extracellular vesicles. let-7 family members present in the CSF mediated neurotoxicity in vitro, albeit to a variable extent. Taken together, neurotoxic let-7 miRNAs are differentially and specifically released in AD, but also in MDE patients. Thus, these miRNAs may mirror common neuropathological paths and by this serve to unscramble mechanisms of different neurodegenerative diseases.
The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). A utoimmune hepatitis and cholangitis are triggered by autoreactive T-cells. Animal models are needed to study the early events in their pathogenesis, namely, the priming of autoreactive T-cells. The requirements for an immune-based animal model are restriction of the immune response to the liver, antigen specificity, and the potential to study the priming of CD8 and CD4 T-cells. Several animal models of autoimmune hepatitis have been developed, 1 none of which fulfills these criteria. Transgenic expression of foreign major histocompatibility complex (MHC) class I molecules in the liver has been widely used. [2][3][4] However, this model has a significant disadvantage: unlike the pathophysiology of an immune or autoimmune reaction, CD8 T cells recognize their antigen on hepatocytes but the antigen is not presented by professional antigen-presenting cells (APCs) in this model. Injection of the synthetic peptide ova p257-264 (SIINFEKL) into mice followed by transfer of antigenspecific CD8 T-cells has also been used, 5 but the possibility of peptide binding to MHC-I molecules on T-cells themselves and their activation by each other 6 or by unrelated cells is a possible concern. Infection with virus expressing ovalbumin 7 results in temporary expression of ovalbumin but also activation of innate immune mechanisms. No animal model exists that allows the simulta-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.